1: Int J Oncol. 2005 Dec;27(6):1727-36. 

Differential gene expression of sulindac-treated human breast epithelial cells.

Roy D, Panda A, Calaf GM, Mitra A.

Biology Department, Brookhaven National Laboratory, Upton, NY 11973, USA.
droy@bnl.gov.

Breast cancer is the most common malignancy and the second major cause of
cancer-related deaths among women in the United States. Recent advances in the
molecular genetics of breast cancer have identified various genes associated
with tumorigenesis. There is evidence that non-steroidal anti-inflammatory
drugs, e.g. sulindac, have some anti-proliferative effects on various tumors
involving altered p53 function. Most of these studies have been performed with
various human colon carcinoma cell lines and few of them focus on non-malignant
proliferative human mammary epithelial cell lines. Therefore, the present study
was undertaken to analyze the differentially expressed genes of the p53
signaling pathway by means of a gene array for the immortalized human breast
epithelial cell line, MCF-10F, treated with sulindac. Out of the total 96 genes,
only 17 were altered by the drug treatment. Among these 17 genes, 6 showed
significant alteration (Q>2.0), whereas 11 genes showed moderate alterations.
Altered genes included BRCA1 associated protein-1 [ubiquitin carboxy-terminal
hydrolase (bap1)]; cell division cycle 2, G1 to S and G2 to M [cdk1(cdc2)]; and
DNA-damage-inducible transcript 1 (gadd45), which were down-regulated. However,
N-myc gene 1 (rtp), promyelocytic leukemia (pml), and nuclear factor of
kappa-light polypeptide gene enhancer in B-cell 3 and p65 [avian (rel A)] were
up-regulated. Northern blot analysis confirmed some of these alterations. The
alteration of p53 signaling pathway gene markers by sulindac treatment can give
us valuable information about the response to drug treatments in a proliferative
cell population.

PMID: 16273229 [PubMed - in process]


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2: Oncogene. 2005 Sep 15;24(41):6231-40. 

Nfkb 1 is dispensable for Myc-induced lymphomagenesis.

Keller U, Nilsson JA, Maclean KH, Old JB, Cleveland JL.

Department of Biochemistry, St Jude Children's Research Hospital, 332 N.
Lauderdale, Memphis, TN 38105, USA.

Rel/NF-kappaB transcription factors are critical arbiters of immune responses,
cell survival, and transformation, and are frequently deregulated in cancer. The
p50 NF-kappaB 1 component of Rel/NF-kappaB DNA-binding dimers regulates genes
involved in both cell cycle traverse and apoptosis. Nfkb 1 loss accelerates B
cell growth and leads to increased B cell turnover in vivo, phenotypes akin to
those manifested in B cells of Emu-Myc transgenic mice, a model of human Burkitt
lymphoma. Interestingly, Emu-Myc B cells express reduced levels of cytoplasmic
and nuclear NF-kappaB 1 and have reduced Rel/NF-kappaB DNA-binding activity,
suggesting that Myc-mediated repression of NF-kappaB 1 might mediate its
proliferative and apoptotic effects on B cells. Furthermore, Nfkb 1 expression
was reduced in the majority of Emu-Myc lymphomas and was also suppressed in
human Burkitt lymphoma. Nonetheless, loss of Nfkb 1 did not appreciably affect
Myc's proliferative or apoptotic responses in B cells and had no effect on
lymphoma development in Emu-Myc mice. Therefore, Nfkb 1 is dispensable for
Myc-induced lymphomagenesis.. Oncogene (2005) 24, 6231-6240

PMID: 15940251 [PubMed - in process]


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3: Nat Genet. 2005 Jun;37(6):579-83. 

Mining for regulatory programs in the cancer transcriptome.

Rhodes DR, Kalyana-Sundaram S, Mahavisno V, Barrette TR, Ghosh D, Chinnaiyan AM.

Department of Pathology, University of Michigan Medical School, Ann Arbor,
Michigan 48109, USA.

DNA microarrays have been widely applied to cancer transcriptome analysis. The
Oncomine database contains a large collection of such data, as well as hundreds
of derived gene-expression signatures. We studied the regulatory mechanisms
responsible for gene deregulation in these cancer signatures by searching for
the coordinate regulation of genes with common transcription factor binding
sites. We found that genes with binding sites for the archetypal cancer
transcription factor, E2F, were disproportionately overexpressed in a wide
variety of cancers, whereas genes with binding sites for other transcription
factors, such as Myc-Max, c-Rel and ATF, were disproportionately overexpressed
in specific cancer types. These results suggest that alterations in pathways
activating these transcription factors may be responsible for the observed gene
deregulation and cancer pathogenesis.

PMID: 15920519 [PubMed - indexed for MEDLINE]


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4: Genes Chromosomes Cancer. 2005 Aug;43(4):414-23. 

Amplification of IGH/MYC fusion in clinically aggressive IGH/BCL2-positive
germinal center B-cell lymphomas.

Martin-Subero JI, Odero MD, Hernandez R, Cigudosa JC, Agirre X, Saez B,
Sanz-Garcia E, Ardanaz MT, Novo FJ, Gascoyne RD, Calasanz MJ, Siebert R.

Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel,
Germany.

Activation of an oncogene via its juxtaposition to the IGH locus by a
chromosomal translocation or, less frequently, by genomic amplification is
considered a major mechanism of B-cell lymphomagenesis. However, amplification
of an IGH/oncogene fusion, coined a complicon, is a rare event in human cancers
and has been associated with poor outcome and resistance to treatment. In this
article are descriptions of two cases of germinal-center-derived B-cell
lymphomas with IGH/BCL2 fusion that additionally displayed amplification of an
IGH/MYC fusion. As shown by fluorescence in situ hybridization, the first case
contained a IGH/MYC complicon in double minutes, whereas the second case showed
a BCL2/IGH/MYC complicon on a der(8)t(8;14)t(14;18). Additional molecular
cytogenetic and mutation analyses revealed that the first case also contained a
chromosomal translocation affecting the BCL6 oncogene and a biallelic
inactivation of TP53. The second case harbored a duplication of REL and acquired
a translocation affecting IGL and a biallelic inactivation of TP53 during
progression. Complicons affecting Igh/Myc have been reported previously in
lymphomas of mouse models simultaneously deficient in Tp53 and in genes of the
nonhomologous end-joining DNA repair pathway. To the best of our knowledge, this
is the first time that IGH/MYC complicons have been reported in human lymphomas.
Our findings imply that the two mechanisms resulting in MYC deregulation, that
is, translocation and amplification, can occur simultaneously. Copyright 2005
Wiley-Liss, Inc.

Publication Types:
    Case Reports

PMID: 15852472 [PubMed - indexed for MEDLINE]


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5: Immunity. 2004 Jul;21(1):19-30. 

The mitogen-induced increase in T cell size involves PKC and NFAT activation of
Rel/NF-kappaB-dependent c-myc expression.

Grumont R, Lock P, Mollinari M, Shannon FM, Moore A, Gerondakis S.

The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade,
Parkville, Victoria 3050, Australia.

Cell growth during the G1 stage of the cell cycle is partly controlled by
inducing c-myc expression, which in B cells is regulated by the NF-kappaB1 and
c-Rel transcription factors. Here, we show that c-myc-dependent growth during T
cell activation requires c-Rel and RelA and that blocking this growth by
inhibiting protein kinase C theta (PKCtheta) coincides with a failure to
upregulate c-myc due to impaired RelA nuclear import and inhibition of
NFAT-dependent c-rel transcription. These results demonstrate that different
Rel/NF-kappaB dimers regulate the mitogenic growth of mature T and B cells, with
a signaling pathway incorporating PKCtheta and NFAT controlling
c-Rel/RelA-induced c-myc expression in activated T cells.

PMID: 15345217 [PubMed - indexed for MEDLINE]


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6: Leuk Lymphoma. 2003;44 Suppl 3:S21-6. 

Pathobiology of primary mediastinal B-cell lymphoma.

Pileri SA, Zinzani PL, Gaidano G, Falini B, Gaulard P, Zucca E, Sabattini E,
Ascani S, Rossi M, Cavalli F; International Extranodal Lymphoma Study Group.

Institute of Haematology Seragnoli, Bologna University, Policinico S. Orsola,
via Massarenti 9, 40138, Bologna, Italy. pileri@med.unibo.it

Controversy still exists over the response to therapy and prognosis of patients
with primary mediastinal B-cell lymphoma (PMBL). Recent data from the
International Extranodal Lymphoma Study Group (IELSG) suggest that a MACOP-B
(methotrexate, adriamycin, cyclophosphamide, vincristine, prednisone, bleomycin)
chemotherapy regimen followed by radiotherapy may be a better induction strategy
than other previously used treatments. Although the pathobiology of PMBL has
been widely studied, its precise histology, phenotype, and molecular
characteristics are still not clear. To date, phenotypic analysis has revealed
the following phenotype: positivity for CD45 and CD20, but negativity for CD3,
CD10, CD21, Class I/II major histocompatibility antigens, and a variety of other
immunohistochemical markers. CD79a is generally detected, despite an absence of
surface immunoglobulins (Igs). CD30 staining is observed in most cases, but is
weaker and less homogeneous than in classic Hodgkin's lymphoma or anaplastic
large cell lymphoma. BCL-2 protein is usually expressed but there are few data
describing the expression of MUM1/IRF4, PAX5/BSAP, BCL-6, or the B-cell
transcription factors BOB.1, Oct-2, and PU.1. Cytogenetic studies reveal gains
in segments of chromosome 9p, including amplification of the REL proto-oncogene
and the tyrosine kinase gene JAK2. Other molecular findings include: C-myc
mutations or rearrangements, p53 mutations, IgV(H), gene mutations, and bcl-2
and mal over-expression. bcl-6 mutations and bcl-2 gene rearrangements are
generally absent, suggesting that PMBL is of pre-germinal center (GC) origin.
However, two recent reports show isotype-switched Ig genes with a high frequency
of somatic hypermutations as well as variants in the 5' noncoding region of the
bcl-6 gene. The IELSG collected 137 PMBL cases for extensive pathologic review.
Histologically, the lymphomatous growth was predominantly diffuse with sclerosis
that induced compartmentalized cell aggregation. It consisted of large cells
with varying degrees of nuclear polymorphism and clear to basophilic cytoplasm.
Molecular analysis was performed on 40 cases and showed novel findings. More
than half of the cases displayed bcl-6 gene mutations, which usually occurred
together with functioning somatic IgV(H) gene mutations, and BCL-6 and/or
MUM1/IRF4 expression. The present study supports the concept that PBML is
derived from activated GC or post-germinal center cells. However, it differs
from other aggressive B-cell lymphomas in that it shows defective Ig production
despite the expression of Oct-2, BOB.1, and PU.1 transcription factors, and a
lack of IgV(H) gene crippling mutations.

Publication Types:
    Review
    Review, Tutorial

PMID: 15202521 [PubMed - indexed for MEDLINE]


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7: J Mol Med. 2004 Sep;82(9):621-8. Epub 2004 Jun 9. 

Stimulation of c-Rel transcriptional activity by PKA catalytic subunit beta.

Yu SH, Chiang WC, Shih HM, Wu KJ.

Institute of Biochemistry, National Yang-Ming University, Taipei 112, Taiwan.

Nuclear factor kappaB (NF-kappaB) is a eukaryotic transcription factor which
responds to different extracellular signals. It is involved in immune response,
inflammation, and cell proliferation. Increased expression of c-Rel (or its
viral homolog v-Rel), one component of the NF-kappaB factors, induces
tumorigenesis in different systems. The activity of NF-kappaB can be regulated
by protein kinase A (PKA) in a cAMP-independent manner. Our previous results
showed that c-MYC induces the activity of PKA by inducing the transcription of
the gene encoding the PKA catalytic subunit beta (PKA-Cbeta). Constitutive
expression of PKA-Cbeta in Rat1a cells induces their transformation. Here we
show that CREB is unlikely to be a phosphorylation target of PKA-Cbeta as
characterized by different cell lines. Electrophoretic mobility shift assays
showed that c-Rel is present as a significant component of the NF-kappaB factors
in c-MYC overexpressing status. The transcriptional activity of c-Rel was
significantly stimulated by PKA-Cbeta. Coactivators p300/CBP are at least
partially responsible for the enhanced activation mediated by c-Rel and
PKA-Cbeta. Interaction between c-Rel and PKA-Cbeta was demonstrated using
coimmunoprecipitation assays. Immunoprecipitation-in vitro phosphorylation
assays showed the direct phosphorylation of c-Rel by PKA-Cbeta. These results
indicate that c-Rel is a reasonable phosphorylation target of PKA-Cbeta, and
that the transcriptional activity of c-Rel is stimulated by PKA-Cbeta possibly
through the interaction with p300/CBP.

PMID: 15197457 [PubMed - indexed for MEDLINE]


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8: Hematology. 2002 Aug;7(4):239-52. 

Molecular heterogeneity of diffuse large B-cell lymphoma: implications for
disease management and prognosis.

Rossi D, Gaidano G.

Hematology Unit, Division of Internal Medicine, Department of Medical Sciences
and IRCAD, Amedeo Avogadro University of Eastern Piedmont, Via Solaroli 17,
I-28100, Novara, Italy.

Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 40% of all
B-cell non-Hodgkin lymphomas of the Western world. According to the "WHO
classification of tumours of the haematopoietic and lymphoid tissues", the term
DLBCL is likely to include more than one disease entity, as suggested by the
marked variability of the clinical presentation and response to treatment of
this disease. Such heterogeneity may reflect the occurrence of distinct
molecular subtypes of DLBCL as well as differences in the host's immune
function. In immunocompetent hosts, approximately 50% DLBCL carry one of two
primary molecular lesions defining two distinct genotypic subgroups,
characterized by activation of either the BCL-6 or the BCL-2 proto-oncogene.
Conversely, the remaining DLBCL of immunocompetent hosts display one of several
molecular lesions, each associated with a small subset of cases and including
activation of the proto-oncogenes REL, MUC-1, BCL-8 and c-MYC. The molecular
pathogenesis of immunodeficiency-associated DLBCL differs substantially from
that of DLBCL in immunocompetent hosts. In fact, EBV infection is present in a
large fraction of immunodeficiency-associated DLBCL, whereas it is consistently
negative in DLBCL of immunocompetent hosts, probably reflecting the critical
role of disruption of the immune system in this disease. Finally, the
application of DNA microarray technology to DLBCL has led to the distinction of
two disease variants: a germinal center like DLBCL and an activated peripheral
B-cell like DLBCL. Overall the molecular features of DLBCL may identify
prognostic categories of the disease and may represent a powerful tool for
therapeutic stratification.

Publication Types:
    Review

PMID: 14972786 [PubMed - indexed for MEDLINE]


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9: Mol Cell Biol. 2003 Aug;23(16):5738-54. 

Mouse mammary tumor virus c-rel transgenic mice develop mammary tumors.

Romieu-Mourez R, Kim DW, Shin SM, Demicco EG, Landesman-Bollag E, Seldin DC,
Cardiff RD, Sonenshein GE.

Department of Biochemistry, Boston University Medical School, Boston,
Massachusetts 02118, USA.

Amplification, overexpression, or rearrangement of the c-rel gene, encoding the
c-Rel NF-kappaB subunit, has been reported in solid and hematopoietic
malignancies. For example, many primary human breast cancer tissue samples
express high levels of nuclear c-Rel. While the Rev-T oncogene v-rel causes
tumors in birds, the ability of c-Rel to transform in vivo has not been
demonstrated. To directly test the role of c-Rel in breast tumorigenesis, mice
were generated in which overexpression of mouse c-rel cDNA was driven by the
hormone-responsive mouse mammary tumor virus long terminal repeat (MMTV-LTR)
promoter, and four founder lines identified. In the first cycle of pregnancy,
the expression of transgenic c-rel mRNA was observed, and levels of c-Rel
protein were increased in the mammary gland. Importantly, 31.6% of mice
developed one or more mammary tumors at an average age of 19.9 months. Mammary
tumors were of diverse histology and expressed increased levels of nuclear
NF-kappaB. Analysis of the composition of NF-kappaB complexes in the tumors
revealed aberrant nuclear expression of multiple subunits, including c-Rel, p50,
p52, RelA, RelB, and the Bcl-3 protein, as observed previously in human primary
breast cancers. Expression of the cancer-related NF-kappaB target genes cyclin
D1, c-myc, and bcl-xl was significantly increased in grossly normal transgenic
mammary glands starting the first cycle of pregnancy and increased further in
mammary carcinomas compared to mammary glands from wild-type mice or virgin
transgenic mice. In transient transfection analysis in untransformed breast
epithelial cells, c-Rel-p52 or -p50 heterodimers either potently or modestly
induced cyclin D1 promoter activity, respectively. Lastly, stable overexpression
of c-Rel resulted in increased cyclin D1 and NF-kappaB p52 and p50 subunit
protein levels. These results indicate for the first time that dysregulated
expression of c-Rel, as observed in breast cancers, is capable of contributing
to mammary tumorigenesis.

PMID: 12897145 [PubMed - indexed for MEDLINE]


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10: Mol Cell Biol. 2003 Apr;23(7):2251-63. 

Lysyl oxidase inhibits ras-mediated transformation by preventing activation of
NF-kappa B.

Jeay S, Pianetti S, Kagan HM, Sonenshein GE.

Department of Biochemistry, Boston University Medical School, Boston,
Massachusetts 02118, USA.

Lysyl oxidase (LO), which catalyzes the oxidation of lysine residues, was
previously shown to have anti-oncogenic activity on ras-transformed cells. Since
oncogenic Ras mediates transformation, in part, through the activation of the
transcription factor nuclear factor-kappa B (NF-kappa B), we tested here the
effects of LO on NF-kappa B activity. Expression of LO in ras-transformed NIH
3T3 cells led to decreased NF-kappa B binding and activity, as well as the
expression of the NF-kappa B target gene c-myc. Importantly, ectopic expression
of LO led to a dramatic decrease in colony formation by ras-transformed NIH 3T3
cells, a finding comparable to the expression of the I kappa B alpha
dominant-negative mutant, which could be rescued by p65/p50 NF-kappa B subunit
expression. LO was unable to directly inhibit the activity of ectopically
expressed p65 and c-Rel NF-kappa B subunits, suggesting that LO affected an
upstream signaling pathway(s) induced by Ras. Consistent with this hypothesis,
LO expression decreased both the rate of I kappa B alpha turnover and the
activities of IKK alpha and IKK beta. Moreover, the ectopic expression of a
constitutively active version of either kinase reversed the negative effects of
LO. Ras can induce NF-kappa B via both the phosphatidylinositol 3-kinase
(PI3K)/Akt and Raf/MEK pathways. LO potently downregulated the PI3K and Akt
kinases, while partially inhibiting MEK kinase activity. Expression of a
constitutively activated, myristylated Akt or PDK1 was able to counteract the
effect of LO on NF-kappa B, whereas constitutively activated Raf was only
partially effective. Importantly, LO blocked membrane localization of Akt and
PDK1 in Ras-transformed cells. Overall, these results strongly argue that the
anti-oncogenic effects of LO on ras-mediated transformation are due to its
ability to inhibit signaling pathways that lead to activation of NF-kappa B.

PMID: 12640111 [PubMed - indexed for MEDLINE]


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11: Oncogene. 2003 Feb 20;22(7):1073-86. 

Functional genomic analysis reveals distinct neoplastic phenotypes associated
with c-myb mutation in the bursa of Fabricius.

Neiman PE, Grbic JJ, Polony TS, Kimmel R, Bowers SJ, Delrow J, Beemon KL.

Divisions of Basic Science and Human Biology, Fred Hutchinson Cancer Research
Center, Seattle, WA 98109, USA. pneiman@fhere.org

Avian retroviral integration into the c-myb locus is casually associated with
the development of lymphomas in the bursa of Farbricius of chickens; these arise
with a shorter latency than bursal lymphomas caused by deregulation of c-myc.
This study indicates that c-myb mutation in embryonic bursal precursors leads to
an oligoclonal population of developing bursal follicles, showing a variable
propensity to form a novel lesion, the neoplastic follicle (NF). About half of
such bursas rapidly developed lymphomas. Detection of changes in gene
expression, during the development of neoplasms, was carried out by cDNA
microarray analysis. The transcriptional signature of lymphomas with mutant
c-myb was more limited than, and only partially shared with, those of bursal
lymphomas caused by Myc or Rel oncogenes. The c-myb-associated lymphomas
frequently showed overexpression of c-myc and altered expression of other genes
involved in cell cycle control and proliferation-related signal transduction.
Oligoclonal, NF-containing bursas lacked detectable c-myc overexpression and
demonstrated a pattern of gene expression distinct from that of normal bursa and
partially shared with the short-latency lymphomas. This functional genomic
analysis uncovered several different pathways of lymphomagenesis by oncogenic
transcription factors acting in a B-cell lineage.

PMID: 12592394 [PubMed - indexed for MEDLINE]


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12: Blood. 2003 Jun 1;101(11):4598-606. Epub 2003 Feb 13. 

The resistance of B-CLL cells to DNA damage-induced apoptosis defined by DNA
microarrays.

Vallat L, Magdelenat H, Merle-Beral H, Masdehors P, Potocki de Montalk G, Davi
F, Kruhoffer M, Sabatier L, Orntoft TF, Delic J.

Direction des Sciences du Vivant-Department de Radiopathologie et Radiobiologie,
Fontenay aux Roses, France.

B-cell chronic lymphoid leukemia (BCLL) is a highly heterogeneous human
malignancy, presumably reflecting specific molecular alterations in gene
expression and protein activity that are thought to underlie the variable
disease outcome. Most B-CLL cell samples undergo apoptotic death in response to
DNA damage. However, a clinically distinct aggressive subset of B-CLL is
completely resistant in vitro to irradiation-induced apoptosis. We therefore
addressed 2 series of microarray analyses on 4 sensitive and 3 resistant B-CLL
cell samples and compared their gene expression patterns before and after
apoptotic stimuli. Data analysis pointed out 16 genes whose expression varied at
least 2-fold specifically in resistant cells. We validated these selected genes
by real-time quantitative reverse transcription-polymerase chain reaction
(RT-PCR) on 7 microarray samples and confirmed their altered expression level on
15 additional B-CLL cell samples not included in the microarray analysis. In
this manner, in 11 sensitive and 11 resistant B-CLL cell samples tested, 13
genes were found to be specific for all resistant samples: nuclear orphan
receptor TR3, major histocompatibility complex (MHC) class II glycoprotein
HLA-DQA1, mtmr6, c-myc, c-rel, c-IAP1, mat2A, and fmod were up-regulated,
whereas MIP1a/GOS19-1 homolog, stat1, blk, hsp27, and ech1 were down-regulated.
In some cases, the expression profile may be dependent on the status of p53.
Some of these genes encode general apoptotic factors but also exhibit lymphoid
cell specificities that could potentially be linked to the development of
lymphoid malignancies (MIP1alpha, blk, TR3, mtmr6). Taken together, our data
define new molecular markers specific to resistant B-CLL subsets that might be
of clinical relevance.

PMID: 12586635 [PubMed - indexed for MEDLINE]


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13: Apoptosis. 2003 Jan;8(1):11-8. 

Roles of the stress-induced gene IEX-1 in regulation of cell death and
oncogenesis.

Wu MX.

Department of Molecular and Cell Biology, Boston University Goldman School of
Dental Medicine, Boston, MA 02118, USA. mxwu@bu.edu

In response to changes in the external environment cells must initiate a
coordinated program of gene expression for them to adapt. IEX-1 (immediate early
response gene X-1) is precisely regulated by multiple transcription factors
among which p53, NF-kappaB/rel, Sp1 and c-Myc play central roles, to ensure
rapid and transient expression of IEX-1 in cells under a variety of stress
conditions. Overexpression of IEX-1 renders some cells sensitive to apoptosis
and accelerates cell cycle progression, but reduces proliferation of other
cells, whereas disruption of IEX-1 expression is associated with decreases in
both apoptosis and cell cycle progression. In sharp contrast to in vitro
studies, in vivo constitutive expression of IEX-1 prevents activated T cells but
not B cells from apoptosis, as shown using IEX-1-transgenic mice that target
IEX-1 expression specifically to lymphocytes driven by the Emu enhancer. The
animals developed a lupus-like disease and subsequently a high incidence of T
cell lymphomas when they aged, due to insufficient apoptosis of T cells. These
varied effects of IEX-1 on cell death and cell cycle progression in a
cell-context dependent fashion implicate that IEX-1 is involved in more than one
signaling pathway, understanding of which will certainly improve our knowledge
with respect to cancer biology, cell death and cell cycle regulation.

Publication Types:
    Review
    Review, Tutorial

PMID: 12510147 [PubMed - indexed for MEDLINE]


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14: Mol Cell. 2002 Dec;10(6):1283-94. 

B cell growth is controlled by phosphatidylinosotol 3-kinase-dependent induction
of Rel/NF-kappaB regulated c-myc transcription.

Grumont RJ, Strasser A, Gerondakis S.

The Walter and Eliza Hall Institute of Medical Research, P.O. Box The Royal
Melbourne Hospital, 3050, Victoria, Australia.

Rel/NF-kappaB transcription factors regulate the division and survival of B
lymphocytes. Here we show that B cells lacking NF-kappaB1 and c-Rel fail to
increase in size upon mitogenic stimulation due to a reduction in induced c-myc
expression. Mitogen-induced B cell growth, although not markedly impaired by
FRAP/mTOR or MEK inhibitors, required phosphatidylinositol 3-kinase (PI3K)
activity. Inhibition of PI3K-dependent growth coincided with a block in the
nuclear import of NF-kappaB1/c-Rel dimers and a failure to upregulate c-myc. In
addition, PI3K was shown to be necessary for a transcription-independent
increase in c-Myc protein levels that accompanies mitogenic activation.
Collectively, these findings establish a role for Rel/NF-kappaB signaling in the
mitogen-induced growth of mammalian cells, which in B lymphocytes requires a
PI3K/c-myc-dependent pathway.

PMID: 12504005 [PubMed - indexed for MEDLINE]


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15: Int J Cancer. 2003 Feb 10;103(4):489-95. 

Hodgkin's lymphoma cell lines are characterized by frequent aberrations on
chromosomes 2p and 9p including REL and JAK2.

Joos S, Granzow M, Holtgreve-Grez H, Siebert R, Harder L, Martin-Subero JI, Wolf
J, Adamowicz M, Barth TF, Lichter P, Jauch A.

German Cancer Research Center, H0700, Im Neuenheimer Feld 280, D-69120
Heidelberg, Germany. s.joos@dkfz-heidelberg.de

Four Hodgkin's lymphoma cell lines (KM-H2, HDLM-2, L428, L1236) were analyzed
for cytogenetic aberrations, applying multiplex fluorescence in situ
hybridization, chromosome banding and comparative genomic hybridization. Each
line was characterized by a highly heterogeneous pattern of karyotypic changes
with a large spectrum of different translocated chromosomes (range 22-57). A
recurrent finding in all cell lines was the presence of chromosomal
rearrangements of the short arm of chromosome 2 involving the REL oncogene
locus. Furthermore, multiple translocated copies of telomeric chromosomal
segments were frequently detected. This resulted in a copy number increase of
putative oncogenes, e.g., JAK2 (9p24) in 3 cell lines, FGFR3 (4p16) and CCND2
(12p13) in 2 cell lines as well as MYC (8q24) in 1 cell line. Our data confirm
previous cytogenetic results from primary Hodgkin's tumors suggesting an
important pathogenic role of REL and JAK2 in this disease. In addition, they
provide evidence for a novel cytogenetic pathomechanism leading to increased
copy numbers of putative oncogenes from terminal chromosomal regions, most
probably in the course of chromosomal stabilization by telomeric capture.
Copyright 2002 Wiley-Liss, Inc.

PMID: 12478664 [PubMed - indexed for MEDLINE]


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16: J Immunol. 2002 Dec 15;169(12):6831-41. 

Peroxisome proliferator-activated receptor gamma-mediated NF-kappa B activation
and apoptosis in pre-B cells.

Schlezinger JJ, Jensen BA, Mann KK, Ryu HY, Sherr DH.

Department of Environmental Health, Boston University School of Public Health,
Boston, MA 02118, USA. jschlezi@bu.edu

The role of peroxisome proliferator-activated receptor gamma (PPARgamma) in
adipocyte physiology has been exploited for the treatment of diabetes. The
expression of PPARgamma in lymphoid organs and its modulation of macrophage
inflammatory responses, T cell proliferation and cytokine production, and B cell
proliferation also implicate it in immune regulation. Despite significant human
exposure to PPARgamma agonists, little is known about the consequences of
PPARgamma activation in the developing immune system. Here, well-characterized
models of B lymphopoiesis were used to investigate the effects of PPARgamma
ligands on nontransformed pro/pre-B (BU-11) and transformed immature B
(WEHI-231) cell development. Treatment of BU-11, WEHI-231, or primary bone
marrow B cells with PPARgamma agonists (ciglitazone and GW347845X) resulted in
rapid apoptosis. A role for PPARgamma and its dimerization partner, retinoid X
receptor (RXR)alpha, in death signaling was supported by 1) the expression of
RXRalpha mRNA and cytosolic PPARgamma protein, 2) agonist-induced binding of
PPARgamma to a PPRE, and 3) synergistic increases in apoptosis following
cotreatment with PPARgamma agonists and 9-cis-retinoic acid, an RXRalpha
agonist. PPARgamma agonists activated NF-kappaB (p50, Rel A, c-Rel) binding to
the upstream kappaB regulatory element site of c-myc. Only doses of agonists
that induced apoptosis stimulated NF-kappaB-DNA binding. Cotreatment with
9-cis-retinoic acid and PPARgamma agonists decreased the dose required to
activate NF-kappaB. These data suggest that activation of PPARgamma-RXR
initiates a potent apoptotic signaling cascade in B cells, potentially through
NF-kappaB activation. These results have implications for the nominal role of
the PPARgamma in B cell development and for the use of PPARgamma agonists as
immunomodulatory therapeutics.

PMID: 12471115 [PubMed - indexed for MEDLINE]


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17: Oncogene. 2002 Oct 3;21(44):6819-28. 

Synergistic and opposing regulation of the stress-responsive gene IEX-1 by p53,
c-Myc, and multiple NF-kappaB/rel complexes.

Huang YH, Wu JY, Zhang Y, Wu MX.

Department of Pathology, Baylor College of Medicine, Houston, Texas, TX 77030,
USA.

NF-kappaB/rel proteins, tumor suppressor p53, and oncogene c-Myc are critical
transcription factors involved in coordinating cellular decision-making events
in response to external stimuli. Consensus sequences for binding these three
transcription factors are found in the promoter region of IEX-1 (Immediate Early
response gene X-1) gene that can either suppress or induce apoptosis in a cell-
and stimulus-dependent manner. Utilizing an electrophoretic mobility shift assay
(EMSA) and a promoter/reporter assay, we show that the NF-kappaB/rel consensus
sequence in the IEX-1 promoter is specifically bound and activated by multiple
NF-kappaB/rel complexes in descending order p65-c-rel-->p65-50-->p50-50.
Interestingly, NF-kappaB/rel-mediated activation of IEX-1 expression was
synergized by p53, but strongly inhibited by c-Myc in a dose-dependent fashion.
Moreover, the ability of c-Myc to inhibit IEX-1 expression requires the presence
of functional p53, which may partially contribute to the varying effects of p53
on IEX-1 expression in different cells. In support of coordinated regulation of
IEX-1 expression by these three transcription factors in vivo, binding of
endogenous p53, c-Myc and NF-kappaB/rel proteins, including p50, p65 and c-rel,
to the IEX-1 promoter was demonstrated in living cells by chromatin
immunoprecipitation using specific antibodies. The study reveals a novel
integrative regulation of specific gene expression by NF-kappaB/rel, p53 and
c-Myc transcription factors.

PMID: 12360408 [PubMed - indexed for MEDLINE]


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18: Br J Cancer. 2002 Sep 23;87(7):779-82. 

High level amplification of N-MYC is not associated with adverse histology or
outcome in primary retinoblastoma tumours.

Lillington DM, Goff LK, Kingston JE, Onadim Z, Price E, Domizio P, Young BD.

Cancer Research UK, Department of Medical Oncology, St Bartholomew's and the
Royal London NHS Trust, London, EC1M 6BQ, UK. D.Lillington@cancer.org.uk

Twenty-five primary retinoblastoma tumours were analysed by real-time
quantitative polymerase chain reaction to determine the genomic copy number of
the N-MYC gene (2p24) relative to the copy number for REL, B2M, ALB, AF10 and
MLL. Twenty-one of these tumours were shown by Comparative Genomic Hybridization
to contain variable copy number increases of chromosomal material mapping to 2p.
High level amplification (>30-fold) of N-MYC was found in three tumours, none of
which showed adverse histological features and all patients are surviving at
between 54 and 108 months post enucleation. Furthermore, the three tumours
associated with metastasis and adverse patient outcome showed normal N-MYC copy
number. Although high level amplification of N-MYC is an unfavourable prognostic
indicator in neuroblastoma, these data show no evidence of a correlation between
amplification of N-MYC and adverse outcome in retinoblastoma.

PMID: 12232763 [PubMed - indexed for MEDLINE]


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19: Biochim Biophys Acta. 2002 May 8;1589(3):247-60. 

Myotrophin-kappaB DNA interaction in the initiation process of cardiac
hypertrophy.

Gupta S, Sen S.

Department of Molecular Cardiology (NB 50), Lerner Research Institute, The
Cleveland Clinic Foundation, 9500 Euclid Avenue, OH 44195, USA.

To investigate how cardiac hypertrophy and heart failure develop, we isolated
and characterized a candidate initiator, the soluble 12-kDa protein myotrophin,
from rat and human hearts. Myotrophin stimulates protein synthesis and
myocardial cell growth associated with increased levels of hypertrophy marker
genes. Recombinant myotrophin from the cloned gene showed structural/functional
motifs, including ankyrin repeats and putative phosphorylation sites for protein
kinase C (PKC) and casein kinase II. One repeat, homologous with I kappaB,
interacts with rel/NF-kappaB in vitro. We analyzed the interaction of
recombinant myotrophin and nuclear extracts prepared from neonatal and adult
cardiomyocytes; gel mobility shift assay showed that myotrophin bound to kappaB
DNA. To define PKC's role in myotrophin-induced myocyte growth, we incubated
neonatal rat myocytes (normal and stretch) with specific inhibitors and found
that myotrophin inhibits [3H]leucine incorporation into myocytes and different
hypertrophic gene expression in neonatal myocytes. Using confocal microscopy, we
observed that a basal level of myotrophin was present in both cytoplasm and
nucleus under normal conditions, but under cyclic stretch, myotrophin levels
became elevated in the nucleus. Myotrophin gene levels were upregulated when
myocytes underwent cyclic stretch or were treated with tumor necrosis
factor-alpha (TNF-alpha) or interleukin-1beta and also when excised beating
hearts were exposed to high pressure. Our data showed that the myotrophin-kappaB
interaction was increased with age in spontaneously hypertensive rats (SHRs)
only. Our data provide evidence that myotrophin-kappaB DNA interaction may be an
important step in initiating cardiac hypertrophy.

PMID: 12031792 [PubMed - indexed for MEDLINE]


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20: J Virol. 2002 Jun;76(11):5737-47. 

RelB-p50 NF-kappa B complexes are selectively induced by cytomegalovirus
immediate-early protein 1: differential regulation of Bcl-x(L) promoter activity
by NF-kappa B family members.

Jiang HY, Petrovas C, Sonenshein GE.

Department of Biochemistry, Boston University School of Medicine, Boston,
Massachusetts 02118-2394, USA.

The NF-kappa B/Rel family has been implicated in control of transcription of the
Bcl-x(L) gene, a target which mediates cell survival signals. The
cytomegalovirus (CMV) immediate-early protein 1 (IE1) was previously shown to
induce NF-kappa B activity. Here, we report that in both vascular smooth muscle
cells (SMCs) and NIH 3T3 cells, surprisingly, IE1 failed to induce Bcl-x(L)
promoter activity, although it induced activity of E8-CAT, a reporter construct
driven by two copies of the NF-kappa B element upstream of the c-myc promoter
(upstream regulatory element [URE]). Thus, the subunit nature of the NF-kappa
B/Rel factors induced by IE1 was examined using immunofluorescence and
immunoblotting. IE1 was found to selectively induce nuclear RelB and p50 in SMCs
and NIH 3T3 cells. An increase in RelB protein mediated by IE1 could, in part,
be related to an increase in steady-state relB mRNA levels. Consistent with this
subunit identification, IE1 was unable to induce E8-CAT activity in relB(-/-)
murine embryonic fibroblast cells. In cotransfection analysis of SMCs and NIH
3T3 cells, RelB and p50 proteins failed to induce Bcl-x(L) promoter activity
while inducing E8-CAT. Furthermore, the NF-kappa B element of the Bcl-x(L)
promoter only weakly bound RelB-p50 complexes compared to the URE NF-kappa B
element. Overall, these findings demonstrate in SMCs and NIH 3T3 cells that the
CMV IE1 protein selectively induces RelB and p50, which fail to activate the
Bcl-x(L) promoter, indicating a strong specificity of binding and activity for
the RelB member of the NF-kappa B family. Furthermore, our results implicate
RelB in CMV infection of cells such as vascular SMCs.

PMID: 11992002 [PubMed - indexed for MEDLINE]


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21: Genes Chromosomes Cancer. 2002 Feb;33(2):114-22. 

Similar patterns of genomic alterations characterize primary mediastinal
large-B-cell lymphoma and diffuse large-B-cell lymphoma.

Palanisamy N, Abou-Elella AA, Chaganti SR, Houldsworth J, Offit K, Louie DC,
Terayu-Feldstein J, Cigudosa JC, Rao PH, Sanger WG, Weisenburger DD, Chaganti
RS.

Laboratory of Cancer Genetics, Cell Biology Program, Sloan-Kettering Institute
for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York
10021, USA.

To address the possible genetic relationship between primary mediastinal
large-B-cell lymphoma (PMLBCL) and diffuse large-B-cell lymphoma (DLBCL), we
compared DNA copy number changes identified by comparative genomic hybridization
(CGH) analysis of 40 PMLBCL and 91 DLBCL tumors. We assessed their karyotypes by
G-banding; amplification of MYC, BCL2, and REL genes by Southern blotting; and
incidence of nonpolymorphic BCL6 mutations by single-strand conformation
polymorphism analysis (SSCP). Overall, CGH identified overlapping and
nonoverlapping patterns of DNA copy number changes in the two groups. Among the
latter changes, gains of chromosomes 8, 11, 15, and 16 and losses of chromosomes
5, 10, 15, 16, 17, and 20 were seen only in DLBCL, and gains of chromosomes 10,
21, and 22 and losses of chromosomes 11, 13, and 18 were seen only in PMLBCL.
Several overlapping changes were identified in both groups, with variation in
incidence. Statistical analysis of these changes showed significant gains of
chromosomes 3 (P <or= 0.05) and 7q (P <or= 0.05) in DLBCL and gains of
chromosomes 9 (P <or= 0.05) and 19 (P <or= 0.05) and the X chromosome (P <or=
0.05) and loss of chromosome 4 (P <or= 0.05) in PMLBCL. Frequent recurring DNA
amplification at 2p13-15 and less frequent amplification at 6p21, 12q13, and
18q21 were noted in both groups. Recurring amplification at 1q21 was seen only
in DLBCL, whereas nonrecurring amplification at 10p11.2 and 15q22-24 was seen
only in PMLBCL. G-banded karyotype analysis identified t(3;14)(q27;q32) in one
and t(14;18)(q32;q21) in two cases of PMLBCL. Seven of 13 cases exhibited SSCP
variants in the 5' noncoding region of BCL6. In addition, 19 of 24 PMLBCLs
assayed for BCL6 protein expression by immunohistochemistry showed positive
results, indicating an origin from a germinal center (GC)-derived B cell. Based
on these data, we conclude that PMLBCL is a distinct entity among GC-derived
high-grade DLBCLs. Copyright 2002 Wiley-Liss, Inc.

PMID: 11793437 [PubMed - indexed for MEDLINE]


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22: Histopathology. 2001 Aug;39(2):163-71. 

Evidence for local immunosuppression and demonstration of c-myc amplification in
pyothorax-associated lymphoma.

Yamato H, Ohshima K, Suzumiya J, Kikuchi M.

Department of Pathology, School of Medicine, Fukuoka University, Nanakuma
7-45-1, Jonanku, Fukuoka 814-0180, Japan.

AIMS: Pyothorax-associated lymphoma (PAL) develops in the pleural cavity of
patients with a long history of pyothorax. Epstein-Barr virus (EBV) is also
involved in PAL, similar to lymphomas in immunodeficient patients. Here we
examined T-lymphocyte subsets as well as c-myc and REL gene amplification in PAL
tissues. METHODS AND RESULTS: We determined the number and distribution of CD4+
and CD8+ T-lymphocytes, to evaluate T-cells in the host immune reaction in seven
cases of PAL. As controls, we also studied 10 cases of extranodal diffuse large
B-cell lymphoma (DLBL) and 10 cases of nodal DLBL. Chromosomal imbalances in PAL
were determined by using comparative genomic hybridization (CGH) analysis. The
mean numbers of CD4+ and CD8+ and their ratio were significantly lower in PAL
than in nodal DLBL. CGH analysis of PAL showed amplification of the 8q24
chromosomal region. In addition, c-myc amplification was found in four cases of
PAL by Southern blot analysis. CONCLUSIONS: Our results suggest that the
development of PAL may involve a local immunosuppressive environment and that
amplification of c-myc might promote tumour progression, as has been described
in the development of Burkitt's lymphoma.

PMID: 11493333 [PubMed - indexed for MEDLINE]


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23: Genes Chromosomes Cancer. 2001 Aug;31(4):316-25. 

Molecular-cytogenetic comparison of mucosa-associated marginal zone B-cell
lymphoma and large B-cell lymphoma arising in the gastro-intestinal tract.

Barth TF, Bentz M, Leithauser F, Stilgenbauer S, Siebert R, Schlotter M, Schlenk
RF, Dohner H, Moller P.

Institute of Pathology, University of Ulm, Albert-Einstein-Allee 11, D-89091
Ulm, Germany. thomas.barth@medizin.uni-ulm.de

Extranodal B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type may
represent a model of lymphoma progression, because a small cell component
frequently occurs in the large cell variants. We studied 52 extranodal B-cell
lymphomas: 18 extranodal marginal zone B-cell lymphomas of MALT type (MZBL,MT),
7 MZBL,MT of the gastro-intestinal tract with a diffuse large B-cell component
(giMZBLplusLBCL), and 27 diffuse large B-cell lymphomas of the gastro-intestinal
tract without small cell component (giLBCL). Analytical techniques were
comparative genomic hybridization (CGH) and fluorescence in situ hybridization
(FISH). The translocation t(11;18) was found as the sole aberration in two
MZBL,MT only. In contrast to this, t(11;18)-negative MZBL,MT were characterized
by frequent gains on chromosome 3 and DNA amplifications on 2p13-p15.
Furthermore, we found a clonal lymphoma progression from the small to the large
cell component with accumulation of gains and losses of chromosomal material in
the large cell component in giMZBLplusLBCL. Aberrations overlapping with MZBL,MT
and giMZBLplusLBCL included losses on chromosome 13, amplifications of the REL
proto-oncogene, or gains on chromosome 12. In addition, the large cell component
revealed gains on 8q24, including amplifications of the MYC proto-oncogene, and
losses on 2q. The giLBCL had frequent gains on chromosomes 12 and 9, as well as
on 11q, and losses on 6q. We conclude that, based on the distinctive and partly
overlapping patterns of genetic aberrations, MALT lymphomas can be divided into
different genetic subgroups. Copyright 2001 Wiley-Liss, Inc.

PMID: 11433522 [PubMed - indexed for MEDLINE]


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24: J Neuroimmunol. 2001 Apr 2;115(1-2):199-202. 

Decreased expression of c-myc family genes in thymuses from myasthenia gravis
patients.

Nagata T, Onodera H, Ohuchi M, Suzuki Y, Tago H, Fujihara K, Ishii N, Sugamura
K, Shoji Y, Handa M, Tabayashi K, Itoyama Y.

Department of Neurology, Tohoku University School of Medicine, 1-1 Seiryo-Machi,
Sendai 980-8574, Aoba, Japan.

The thymus is a critical organ for the elimination of autoreactive T cells by
apoptosis. We studied the expression of apoptosis-associated genes, bcl-xL, bad,
caspase-3, and c-myc family genes in myasthenia gravis (MG) thymuses. We
observed that the mRNA levels of myc family genes, c-myc and max, were markedly
reduced in MG thymuses. These results indicate that c-myc-mediated signaling is
abnormal in MG thymuses. The levels of molecules whose expressions are
associated with myc, such as STAM, prothymosin-alpha, and NFkappaB, were also
analyzed.

Publication Types:
    Clinical Trial

PMID: 11282171 [PubMed - indexed for MEDLINE]


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25: J Virol. 2001 Jan;75(1):215-25. 

Role of NF-kappaB and myc proteins in apoptosis induced by hepatitis B virus HBx
protein.

Su F, Theodosis CN, Schneider RJ.

Department of Microbiology, New York University School of Medicine, New York,
New York 10016, USA.

Chronic infection with hepatitis B virus (HBV) promotes a high level of liver
disease and cancer in humans. The HBV HBx gene encodes a small regulatory
protein that is essential for viral replication and is suspected to play a role
in viral pathogenesis. HBx stimulates cytoplasmic signal transduction pathways,
moderately stimulates a number of transcription factors, including several
nuclear factors, and in certain settings sensitizes cells to apoptosis by
proapoptotic stimuli, including tumor necrosis factor alpha (TNF-alpha) and
etopocide. Paradoxically, HBx activates members of the NF-kappaB transcription
factor family, some of which are antiapoptotic in function. HBx induces
expression of Myc protein family members in certain settings, and Myc can
sensitize cells to killing by TNF-alpha. We therefore examined the roles of
NF-kappaB, c-Myc, and TNF-alpha in apoptotic killing of cells by HBx.
RelA/NF-kappaB is shown to be induced by HBx and to suppress HBx-mediated
apoptosis. HBx also induces c-Rel/NF-kappaB, which can promote apoptotic cell
death in some contexts or block it in others. Induction of c-Rel by HBx was
found to inhibit its ability to directly mediate apoptotic killing of cells.
Thus, HBx induction of NF-kappaB family members masks its ability to directly
mediate apoptosis, whereas ablation of NF-kappaB reveals it. Investigation of
the role of Myc protein demonstrates that overexpression of Myc is essential for
acute sensitization of cells to killing by HBx plus TNF-alpha. This study
therefore defines a specific set of parameters which must be met for HBx to
possibly contribute to HBV pathogenesis.

PMID: 11119591 [PubMed - indexed for MEDLINE]


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26: Oncogene. 2000 Nov 16;19(48):5498-506. 

The RelA NF-kappaB subunit and the aryl hydrocarbon receptor (AhR) cooperate to
transactivate the c-myc promoter in mammary cells.

Kim DW, Gazourian L, Quadri SA, Romieu-Mourez R, Sherr DH, Sonenshein GE.

Department of Biochemistry, Women's Health, Boston University School of
Medicine, Massachusetts 02118, USA.

NF-kappaB/Rel transcription factors regulate many genes involved in control of
cellular proliferation, neoplastic transformation, and apoptosis, including the
c-myc oncogene. Recently, we have observed that levels of NF-kappaB and aryl
hydrocarbon receptor (AhR), which mediates malignant transformation by
environmental carcinogens, are highly elevated and appear constitutively active
in breast cancer cells. Rel factors have been found to functionally interact
with other transcription factors. Here we demonstrate a physical and functional
association between the RelA subunit of NF-kappaB and AhR resulting in the
activation of c-myc gene transcription in breast cancer cells. RelA and AhR
proteins were co-immunoprecipitated from cytoplasmic and nuclear extracts of
non-malignant MCF-10F breast epithelial and malignant Hs578T breast cancer
cells. In transient co-transfection, RelA and AhR gene products demonstrated
cooperation in transactivation of the c-myc promoter, which was dependent on the
NF-kappaB elements, and in induction of endogenous c-Myc protein levels. A novel
AhR/RelA-containing NF-kappaB element binding complex was identified by
electrophoretic mobility shift analysis of nuclear extracts from RelA and AhR
co-transfected Hs578T cells. Thus, the RelA and AhR proteins functionally
cooperate to bind to NF-kappaB elements and induce c-myc gene expression. These
findings suggest a novel signaling mechanism whereby the Ah receptor can
stimulate proliferation and tumorigenesis of mammary cells.

PMID: 11114727 [PubMed - indexed for MEDLINE]


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27: J Biol Chem. 2000 Oct 13;275(41):32338-46. 

NF-kappa B activity is required for the deregulation of c-myc expression by the
immunoglobulin heavy chain enhancer.

Kanda K, Hu HM, Zhang L, Grandchamps J, Boxer LM.

Center for Molecular Biology in Medicine, Veterans Affairs Palo Alto Health Care
System and the Department of Medicine, Stanford University School of Medicine,
Stanford, California 94305, USA.

The c-myc gene is translocated to one of the immunoglobulin genes in Burkitt's
lymphoma resulting in deregulated expression of c-myc. Several enhancers have
been shown to be important for expression of the immunoglobulin heavy chain
gene. Four enhancer regions (murine-hypersensitive sites (MHS) 1, 2, 3, and 4)
located 3' of the murine immunoglobulin heavy chain gene play a role in
activating expression of the translocated c-myc gene. The enhancer regions also
result in a shift in transcriptional initiation from the P2 promoter to P1 that
is characteristic of the translocated c-myc allele. We found that the most 3'
enhancer region (MHS4) activated the c-myc promoter by 46-fold in the Raji
Burkitt's lymphoma cell line, and it was the most active enhancer in these
cells. The addition of enhancer regions MHS1,2 and 3 to MHS4 increased c-myc
transcription by an additional 3-fold and resulted in the full promoter shift
from P2 to P1. By deletion analysis of enhancer region MHS4, we located a region
that was critical for the transcriptional activity of MHS4. Electrophoretic
mobility shift assay analysis revealed that NF-kappaB/Rel family members bound
to this region. Mutation of the NF-kappaB binding site abolished both the
enhancer activity and the promoter shift activity of MHS4. An active NF-kappaB
site was also identified in the human HS4 enhancer. Inhibition of c-myc promoter
activity driven by the immunoglobulin enhancers was observed with expression of
a super-repressor IkappaBalpha construct. These results indicate that the
NF-kappaB/Rel transcription factors play an important role in the deregulation
of the translocated c-myc gene in Burkitt's lymphoma and suggest that
interference with NF-kappaB function may represent a new approach to the
treatment of Burkitt's lymphoma.

PMID: 10931834 [PubMed - indexed for MEDLINE]


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28: Hum Pathol. 2000 Jul;31(7):871-3. 

Common-variable immunodeficiency-related lymphomas associate with mutations and
rearrangements of BCL-6: pathogenetic and histogenetic implications.

Ariatti C, Vivenza D, Capello D, Migliazza A, Parvis G, Fassone L, Buonaiuto D,
Savinelli F, Rossi D, Saglio G, Gaidano G.

Department of Medical Sciences, Amedeo Avogadro University of Eastern Piedmont,
Novara, Italy.

Common-variable immunodeficiency (CVI) patients develop non-Hodgkin's lymphomas
(NHL), mainly B-lineage diffuse large-cell lymphomas (DLCL), with a high
relative risk. The molecular pathogenesis of CVI-related NHL (CVI-NHL) is
unknown. Here we aimed at providing a detailed molecular characterization of
CVI-NHL. Rearrangements of BCL-6 were detected in two thirds of CVI-NHL cases
examined. All 3 CVI-NHL also harbored point mutations of the BCL-6 5' noncoding
regions, which constitute a marker of B-cell transit through the germinal center
(GC). The number and molecular pattern of BCL-6 mutations in CVI-NHL were
similar to that detected in DLCL of immunocompetent hosts and in DLCL arising in
other immunodeficiency settings. Microsatellite instability occurred in one
CVI-NHL devoid of a BCL-6 rearrangement. All CVI-NHL scored negative for genetic
lesions of BCL-2, p53, c-MYC, REL as well as for viral infection by EBV and
HHV-8. Overall, these data indicate that: similarly to other
immunodeficiency-related NHL, involvement of BCL6 occurs frequently also in
CVI-NHL; and because BCL-6 mutations are acquired by B cells during GC transit,
their occurrence in CVI-NHL suggest that these lymphomas are histogenetically
related to GC B cells.

Publication Types:
    Case Reports

PMID: 10923927 [PubMed - indexed for MEDLINE]


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29: Gene. 2000 Jun 27;251(2):175-86. 

Gene structure and promoter for Crad2 encoding mouse
cis-retinol/3alpha-hydroxysterol short-chain dehydrogenase isozyme.

Tomita K, Sato M, Kajiwara K, Tanaka M, Tamiya G, Makino S, Tomizawa M, Mizutani
A, Kuwano Y, Shiina T, Ishii H, Kimura M.

Department of Molecular Life Science, School of Medicine, Tokai University,
Bohseidai, Isehara, 259-1193, Kanagawa, Japan.

Cis-retinol/androgen dehydrogenase type 2 (CRAD2) has been shown to catalyze the
dehydrogenation of retinols, including 9-cis retinol, and also to exhibit
3alpha- and 17beta- hydroxysteroid dehydrogenase activities. To examine the
function of this enzyme and regulation of its gene, the Crad2 gene was cloned
from a mouse genomic DNA library and characterized. The complete mouse
CRAD2-coding region was found in four exons spanning an approximately 5kb
region. The nucleotide sequences of the exons encoding 316 amino acids were
identical to those of the previously reported mouse Crad2 cDNA. Primer extension
analysis and RNase protection assay were used to map the major transcription
initiation sites to the positions lying 87 and 89 base pairs upstream of the ATG
translation start codon. The region proximal to the initiation sites exhibited
the absence of both TATAA and CAAT boxes. This region had hepatocyte nuclear
factor binding sites, consistent with its predominant expression in the liver.
Computer analysis of an approximately 7.5kb 5'-flanking region also suggested
the presence of binding sites for AP-1, SREBP1, HSF2, c-Rel, c-Myc, CREBP, GATA,
Ets, E2F, and Oct-1, suggesting that various factors including retinoic acid,
cholesterol, various kinds of stress, the cell cycle, and cyclic AMP may
regulate the expression of this gene. Fluorescence in-situ hybridization
analysis showed that Crad2 is located at the terminus of mouse chromosome 10, an
area that corresponds to band 10D3, suggesting that RDH-related SDRs may be
located together in the cluster locus. Northern blot hybridization and RT-PCR
analysis demonstrated that CRAD2 was expressed not in early embryonic stages,
and not in embryonic stem cells, but instead in the gastrointestinal tract
during later embryonic development and adult stage. In conclusion, we have
presented the first complete structural analysis, including that of the promoter
and chromosomal location, of a member of the retinol/androgen dehydrogenase
subfamily of the group of the short-chain dehydrogenase/reductase (SDR)
isozymes. Our findings will provide the basis for in-vitro or in-vivo studies
concerning the regulation of retinol and androgen metabolism and enable
determination of the mechanism of diseases related to retinol, retinal, retinoic
acid, and androgen.

PMID: 10876094 [PubMed - indexed for MEDLINE]


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30: Carcinogenesis. 2000 May;21(5):871-9. 

Activation of NF-kappaB/Rel occurs early during neoplastic transformation of
mammary cells.

Kim DW, Sovak MA, Zanieski G, Nonet G, Romieu-Mourez R, Lau AW, Hafer LJ, Yaswen
P, Stampfer M, Rogers AE, Russo J, Sonenshein GE.

Department of Biochemistry, Department of Pathology and Laboratory Medicine and
Program in Research on Women's Health, Boston University Medical School, 715
Albany Street, Boston, MA 02118, USA.

NF-kappaB/Rel is a family of transcription factors which are expressed in all
cells; however, in most non-B cells, they are sequestered in the cytoplasm in
inactive complexes with specific inhibitory proteins, termed IkappaBs. We have
recently shown that NF-kappaB/Rel factors are aberrantly activated in human
breast cancer and rodent mammary tumors, and function to promote tumor cell
survival and proliferation. Here, we have examined the time-course of induction
of NF-kappaB/Rel factors upon carcinogen treatment of female Sprague-Dawley
(S-D) rats in vivo and in human mammary epithelial cells (HMECs) in culture. We
observed that NF-kappaB/Rel activation is an early event, occurring prior to
malignant transformation. In S-D rats, increased NF-kappaB/Rel binding was
detected in nuclear extracts of mammary glands from 40% of animals 3 weeks
post-treatment with 15 mg/kg 7,12-dimethylbenz[a]anthracene (DMBA); this is
prior to formation of tumors which normally begin to be detected after 7-9
weeks. In non-tumorigenic MCF-10F cells, in vitro malignant transformation upon
treatment with either DMBA or benzo[a]pyrene (B[a]P) resulted in a 4- to 12-fold
increase in activity of classical NF-kappaB (p65/p50). NF-kappaB induction was
corrrelated with a decrease in the stability of the NF-kappaB-specific
inhibitory protein IkappaB-alpha. Ectopic expression of the transactivating p65
subunit of NF-kappaB in MCF-10F cells induced the c-myc oncogene promoter, which
is driven by two NF-kappaB elements, and endogenous c-Myc levels. Furthermore,
reduction mammoplasty-derived HMECs, immortalized following B[a]P exposure,
showed dysregulated induction of classical NF-kappaB prior to malignant
transformation. Together these findings suggest that activation of NF-kappaB
plays an early, critical role in the carcinogen-driven transformation of mammary
glands.

PMID: 10783306 [PubMed - indexed for MEDLINE]


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31: J Neurochem. 2000 Feb;74(2):647-58. 

Kainic acid-induced apoptosis in rat striatum is associated with nuclear
factor-kappaB activation.

Nakai M, Qin ZH, Chen JF, Wang Y, Chase TN.

Experimental Therapeutics Branch, National Institute of Neurological Disorders
and Stroke, NIH, Bethesda, Maryland 20892-1406, USA.

The present study evaluated whether nuclear factor-kappaB (NF-kappaB) activation
contributes to the apoptotic-like death of striatal neurons induced by kainic
acid (KA) receptor stimulation. Intrastriatally infused KA (1.25-5.0 nmol)
produced substantial neuronal loss as indicated by an 8-73% decrease in 67-kDa
glutamic acid decarboxylase (p<0.05). KA (1.25-5.0 nmol) elicited
internucleosomal DNA fragmentation that was inhibited by the AMPA/KA receptor
antagonist NBQX
(1,2,3,4-tetrahydro-6-nitro-2,3-dibenzo[f]quinoxaline-7-sulfonamide) but not by
the NMDA receptor antagonist MK-801. A decrease in IkappaB-alpha protein levels,
which was accompanied by an increase in NF-kappaB binding activity, was found
from 6 to 72 h after KA (2.5 nmol) infusion. NF-kappaB was composed mainly of
p65 and c-Rel as revealed by supershift assay. In addition, c-Myc and p53
increased from five- to sevenfold from 24 to 72 h after KA (2.5 nmol)
administration. Immunohistochemistry revealed high levels of c-Myc and p53
immunoreactivity, mainly in medium-sized striatal neurons. Pretreatment with the
cell-permeable recombinant peptide NF-kappaB SN50 (5-20 microg) blocked
NF-kappaB nuclear translocation, but had no effect on AP-1 binding. NF-kappaB
SN50 also inhibited the KA-induced up-regulation of c-Myc and p53, as well as
internucleosomal DNA fragmentation. The apoptotic-like destruction of rat
striatal neurons induced by KA receptor stimulation thus appears to involve
biochemical mechanisms similar to those mediating the excitotoxic response to
NMDA receptor stimulation. The present results provide additional support for
the view that NF-kappaB activation contributes to c-Myc and p53 induction and
subsequent apoptosis in an excitotoxic model of Huntington's disease.

PMID: 10646516 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


32: Cell Growth Differ. 1999 May;10(5):287-94. 

Nuclear factor kappaB cooperates with c-Myc in promoting murine hepatocyte
survival in a manner independent of p53 tumor suppressor function.

Bellas RE, Sonenshein GE.

Department of Biochemistry, Boston University School of Medicine, Massachusetts
02118, USA.

The nuclear factor-kappaB (NF-kappaB)/Rel family of transcription factors has
been implicated in promoting hepatocyte survival during development and liver
regeneration following partial hepatectomy. Inhibition of NF-kappaB/Rel activity
by microinjection of the specific inhibitor IkappaB-alpha induces apoptosis in a
nontransformed normal murine hepatocyte (NMH) cell line. Here, we demonstrate
that apoptosis resulting from such inhibition requires down-regulation of the
c-Myc proto-oncoprotein and occurs independently of p53 tumor suppressor
function. NMH cells plated at low density displayed low sensitivity to
IkappaB-alpha-induced apoptosis and high levels of c-Myc protein expression.
Comicroinjection of IkappaB-alpha with the c-Myc antagonist Mad1-glutathione
S-transferase fusion protein greatly enhanced cell death. In addition, transient
cotransfection of low-density NMH and AML12 hepatocytes with vectors expressing
IkappaB-alpha and antisense c-myc transcripts promoted cell death. Conversely,
ectopic c-myc expression significantly decreased the extent of cell death in NMH
cells plated at saturating density, which were characterized by very low levels
of c-Myc and high susceptibility to NF-kappaB inhibition-induced cell death.
Finally, IkappaB-alpha-induced apoptosis was unaffected in NMH cells expressing
a dominant negative p53 protein. Thus, NF-kappaB cooperates with c-Myc in
promoting murine hepatocyte survival in a manner independent of p53 tumor
suppressor activity.

PMID: 10359010 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


33: J Neurosci. 1999 May 15;19(10):4023-33. 

Nuclear factor kappaB nuclear translocation upregulates c-Myc and p53 expression
during NMDA receptor-mediated apoptosis in rat striatum.

Qin ZH, Chen RW, Wang Y, Nakai M, Chuang DM, Chase TN.

Experimental Therapeutics Branch, National Institute of Mental Health, National
Institutes of Health, Bethesda, Maryland 20892, USA.

Nuclear factor kappaB (NF-kappaB) appears to participate in the
excitotoxin-induced apoptosis of striatal medium spiny neurons. To elucidate
molecular mechanisms by which this transcription factor contributes to NMDA
receptor-triggered apoptotic cascades in vivo, rats were given the NMDA receptor
agonist quinolinic acid (QA) by intrastriatal infusion, and the role of
NF-kappaB in the induction of apoptosis-related genes and gene products was
evaluated. QA administration induced time-dependent NF-kappaB nuclear
translocation. The nuclear NF-kappaB protein after QA treatment was comprised
mainly of p65 and c-Rel subunits as detected by gel supershift assay. Levels of
c-Myc and p53 mRNA and protein were markedly increased at the time of QA-induced
NF-kappaB nuclear translocation. Immunohistochemical analysis showed that c-Myc
and p53 induction occurred in the excitotoxin-sensitive medium-sized striatal
neurons. NF-kappaB nuclear translocation was blocked in a dose-dependent manner
by the cell-permeable recombinant peptide NF-kappaB SN50, but not by the
NF-kappaB SN50 control peptide. NF-kappaB SN50 significantly inhibited the
QA-induced elevation in levels of c-Myc and p53 mRNA and protein. Pretreatment
or posttreatment with NF-kappaB SN50, but not the control peptide, also
substantially reduced the intensity of QA-induced internucleosomal DNA
fragmentation. The results suggest that NF-kappaB may promote an apoptotic
response in striatal medium-sized neurons to excitotoxic insult through
upregulation of c-Myc and p53. This study also provides evidence indicating an
unique signaling pathway from the cytoplasm to the nucleus, which regulates p53
and c-Myc levels in these neurons during apoptosis.

PMID: 10234031 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


34: Biochim Biophys Acta. 1999 Jan 11;1448(3):425-38. 

NSAIDs and butyrate sensitize a human colorectal cancer cell line to TNF-alpha
and Fas ligation: the role of reactive oxygen species.

Giardina C, Boulares H, Inan MS.

Department of Molecular and Cell Biology, University of Connecticut, Storrs
06269-3125, USA. giardina@uconnvm.uconn.edu

The nonsteroidal antiinflammatory drugs (NSAIDs) indomethacin and salicylic acid
and the short chain fatty acid butyrate are effective colon cancer
chemopreventive agents that increase reactive oxygen species (ROS) generation in
colon cancer cells. Here we demonstrate that these agents sensitize the normally
resistant human HT-29 colon cancer cell line to apoptosis induced by TNF-alpha
or a Fas ligating antibody. The role of ROS in this sensitization is supported
by the finding that direct exposure of the cells to H2O2 is sufficient for
sensitization. Neither TNF-alpha nor Fas ligation alter basal or chemopreventive
agent-activated ROS generation, suggesting that the death ligands and
chemopreventive agents act in a complementary fashion. The dual chemopreventive
agent/death ligand treatments do not increase Fas, TNF receptor 1, Bak or c-myc
expression (although salicylic acid moderately induces of Fas expression). Cell
death does correlate with alterations in NF-kappa B activity: the NSAIDs,
butyrate and H2O2 enhance c-Rel complex formation by TNF-alpha and provide an
overall enhancement of NF-kappa B activation by Fas. The antioxidant
N-acetylcysteine (NAC) blocks cell death and NF-kappa B activation induced by
Fas ligation, suggesting a potential role for NF-kappa B in Fas-induced
apoptosis in these cells. The effects of NAC on TNF-alpha-induced cell death are
more complex, with NAC being marginally protective and itself enhancing the
formation of c-Rel containing complexes at higher concentrations (25 mM). The
influence of NSAIDs and butyrate on ROS generation and death ligand sensitivity
may be relevant to their ability to suppress colon carcinogenesis.

PMID: 9990295 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


35: J Natl Cancer Inst. 1999 Jan 20;91(2):135-43. 

Comment in:
    J Natl Cancer Inst. 1999 Jan 20;91(2):104-6.

Induction of programmed cell death in Kaposi's sarcoma cells by preparations of
human chorionic gonadotropin.

Samaniego F, Bryant JL, Liu N, Karp JE, Sabichi AL, Thierry A, Lunardi-Iskandar
Y, Gallo RC.

Institute of Human Virology, Medical Biotechnology Center and Greenebaum Cancer
Center, University of Maryland, Baltimore 21201-1192, USA. samanieg@umbi.umd.edu

BACKGROUND: Isolation of the first neoplastic acquired immunodeficiency
syndrome-related Kaposi's sarcoma (KS) cell line (KS Y-1) has furthered
understanding of the pathogenesis of KS. Studies with KS Y-1 cells have
indicated that inhibition of KS cell proliferation occurs in early pregnancy in
mice and after treatment with certain commercial preparations of human chorionic
gonadotropin (hCG, a pregnancy hormone purified from urine). The activity of the
commercial preparations has been attributed to an hCG-associated factor(s)
(HAF). While several clinical benefits of HAF are clearly evident, the basis for
its anti-KS properties remains unknown. We investigated the apoptosis-inducing
effects of HAF and the expression of apoptosis-related proteins in KS cells.
METHODS: KS Y-1 and KS SLK cells were treated with clinical-grade crude
preparations of hCG, recombinant hCG, or urine fractions exhibiting anti-KS
activity and then examined for features of apoptosis. Levels of proteins
associated with apoptosis were monitored by western blot analysis, and cell DNA
content was assessed by flow cytometry. Tumors induced in mice by inoculation of
KS Y-1 cells were treated with preparations of hCG, and the tumors were examined
for cell morphology and also for DNA fragmentation by use of the terminal
deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine triphosphate
nick-end-labeling (TUNEL) assay. RESULTS: The HAF present in some preparations
of hCG and in urine fractions has the ability to induce apoptosis in KS cells in
vitro and in vivo. HAF-triggered apoptosis was preceded by increased levels of
the apoptosis-related proteins c-Myc and c-Rel and cell accumulation in Go/G1
phase of the cell cycle. KS Y-1 cells transfected with a c-Myc complementary DNA
showed elevated rates of apoptosis. CONCLUSION: The anti-KS activity of HAF
appears to induce apoptosis. Such activity suggests a role for HAF in
pregnancy-related regulation of cell death.

PMID: 9923854 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


36: Blood. 1998 Jul 1;92(1):234-40. 

Chromosomal and gene amplification in diffuse large B-cell lymphoma.

Rao PH, Houldsworth J, Dyomina K, Parsa NZ, Cigudosa JC, Louie DC, Popplewell L,
Offit K, Jhanwar SC, Chaganti RS.

Cell Biology Program and the Departments of Pathology and Human Genetics,
Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Chromosomal translocations leading to deregulation of specific oncogenes
characterize approximately 50% of cases of diffuse large B-cell lymphomas
(DLBL). To characterize additional genetic features that may be of value in
delineating the clinical characteristics of DLBL, we studied a panel of 96 cases
at diagnosis consecutively ascertained at the Memorial Sloan-Kettering Cancer
Center (MSKCC) for incidence of gene amplification, a genetic abnormality
previously shown to be associated with tumor progression and clinical outcome. A
subset of 20 cases was subjected to comparative genomic hybridization (CGH)
analysis, which identified nine sites of chromosomal amplification (1q21-23,
2p12-16, 8q24, 9q34, 12q12-14, 13q32, 16p12, 18q21-22, and 22q12). Candidate
amplified genes mapped to these sites were selected for further analysis based
on their known roles in lymphoid cell and lymphoma development, and/or history
of amplification in tumors. Probes for six genes, which fulfilled these
criteria, REL (2p12-16), MYC (8q24), BCL2 (18q21), GLI, CDK4, and MDM2
(12q13-14), were used in a quantitative Southern blotting analysis of the 96
DLBL DNAs. Each of these genes was amplified (four or more copies) with
incidence ranging from 11% to 23%. This analysis is consistent with our previous
finding that REL amplification is associated with extranodal presentation. In
addition, BCL2 rearrangement and/or REL, MYC, BCL2, GLI, CDK4, and MDM2
amplification was associated with advanced stage disease. These data show, for
the first time, that amplification of chromosomal regions and genes is a
frequent phenomenon in DLBL and demonstrates their potential significance in
lymphomagenesis.

PMID: 9639522 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


37: Blood. 1998 Jun 1;91(11):4321-30. 

Characteristic pattern of chromosomal gains and losses in primary large B-cell
lymphomas of the gastrointestinal tract.

Barth TF, Dohner H, Werner CA, Stilgenbauer S, Schlotter M, Pawlita M, Lichter
P, Moller P, Bentz M.

Medizinische Klinik und Poliklinik V, Universitat Heidelberg, Heidelberg,
Germany.

In contrast to low-grade B-cell lymphomas originating in the gastrointestinal
(GI) tract, only few cytogenetic data are available for the large cell, highly
malignant variants. We studied 31 large B-cell lymphomas of the GI tract by
comparative genomic hybridization (CGH) and fluorescence in situ hybridization
using specific DNA probes (FISH). The most frequent aberrations were gains of
all or of parts of chromosomes 11 (11 cases), 12 (9 cases), 1q (4 cases), and 3q
(4 cases). Losses of parts of chromosome 6q and of parts of the short arm of
chromosome 17 (6 cases each) were found most frequently. In four cases a total
of seven high-level DNA amplifications was detected. In two of these cases,
involvement of specific protooncogenes (REL and MYC) was shown. Some genetic
aberrations seemed to be associated with an inferior clinical course: patients
with >/=2 aberrations had a significantly shorter median survival. Furthermore,
all patients with gains of all or parts of chromosome arm 1q and with high-level
DNA amplifications as well as seven of nine patients with gains of all or parts
of chromosome 12 died of lymphoma. In conclusion, the pattern of chromosomal
gains and losses in large B-cell lymphomas was different from data reported for
low-grade (MALT) lymphomas of the stomach and bowel, especially with respect to
the high incidence of partial gains of chromosome arm 11q and of all or parts of
chromosome 12 and the low frequency of polysomy 3. In addition, our data suggest
that chromosomal gains and losses detected by CGH and FISH may predict for the
outcome of patients with this tumor entity.

PMID: 9596681 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


38: Blood. 1998 Jun 1;91(11):4136-44. 

NF-kappaB transcription factors are involved in normal erythropoiesis.

Zhang MY, Sun SC, Bell L, Miller BA.

Department of Pediatrics, Pennsylvania State University College of Medicine,
Milton S. Hershey Medical Center, Hershey, PA 17033-0850, USA.

NF-kappaB/Rel designates a widely distributed family of transcription factors
involved in immune and acute phase responses. Here, the expression and function
of NF-kappaB factors in erythroid proliferation and differentiation were
explored. In an erythroleukemia cell line, TF-1, high levels of p105/p50,
p100/p52, p65, and IkappaBalpha were detected 24 hours after growth factor
deprivation. In response to granulocyte-macrophage colony-stimulating factor
(GM-CSF) stimulation, significant induction of p52 expression was observed.
GM-CSF also induced nuclear translocation of both p52 and p65. No induction of
NF-kappaB factors was observed with erythropoietin stimulation of TF-1 cells.
Overexpression of p52 and p65 in TF-1 cells by transient transfection resulted
in significant induction of a kappaB-TATA-luciferase reporter plasmid, showing
that these factors are functional in vivo in erythroid cells. To determine
whether NF-kappaB factors may play a role in normal erythropoiesis, levels of
these factors were determined in burst-forming unit-erythroid (BFU-E)-derived
cells at different stages of differentiation. The NF-kappaB factors p105/p50,
p100/p52, and p65 were highly expressed in early BFU-E-derived precursors, which
are rapidly proliferating, and declined during maturation. Furthermore, nuclear
levels of NF-kappaB factors p50, p52, and p65 were higher in less mature
precursors (day 10 BFU-E-derived cells) compared with more differentiated (day
14) erythroblasts. In nuclear extracts from day 10 BFU-E-derived cells, p50,
p52, and p65 were able to form complexes, which bound to kappaB sites in the
promoters of both the c-myb and c-myc genes, suggesting that c-myb and c-myc may
be among the kappaB-containing genes regulated by NF-kappaB factors in normal
erythroid cells. Taken together, these data show that NF-kappaB factors are
modulated by GM-CSF and suggest they function to regulate specific kappaB
containing genes involved in erythropoiesis.

PMID: 9596659 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


39: J Immunol. 1998 Feb 1;160(3):1240-5. 

CpG DNA rescue from anti-IgM-induced WEHI-231 B lymphoma apoptosis via
modulation of I kappa B alpha and I kappa B beta and sustained activation of
nuclear factor-kappa B/c-Rel.

Yi AK, Krieg AM.

Department of Internal Medicine, University of Iowa College of Medicine, Iowa
City 52242, USA.

Unmethylated CpG dinucleotides in particular base contexts in oligonucleotides
(CpG DNA) rescue WEHI-231 cells from anti-IgM-induced cell cycle arrest and
apoptosis. Anti-IgM rapidly elevated the levels of NFkappaB p50/c-Rel
heterodimers followed by a decline of p50/c-Rel heterodimers by 3 h and a
concomitant increase of p50/p50 homodimers. In contrast, CpG DNA induced and
maintained the levels of p50/c-Rel heterodimers in the presence or absence of
anti-IgM, while control non-CpG DNA failed to induce NFkappaB activation.
Anti-IgM induced IkappaB alpha degradation followed by increased IkappaB alpha
protein levels. The levels of IkappaB beta were increased after anti-IgM
treatment. In contrast, CpG DNA, but not non-CpG DNA, induced sustained IkappaB
alpha and IkappaB beta degradation in the presence or absence of anti-IgM.
Inhibition of IkappaB degradation blocked CpG DNA-induced NFkappaB activation
and expression of c-myc. Prevention of NFkappaB activation by inhibiting IkappaB
degradation also suppressed the ability of CpG DNA to rescue WEHI-231 cells from
anti-IgM-induced apoptosis. These results indicate that CpG DNA-mediated
sustained activation of NFkappaB depends on the degradation of IkappaB alpha and
IkappaB beta and is required for the CpG DNA-mediated anti-apoptosis gene
expression and the protection against anti-IgM-induced apoptosis of WEHI-231
cells.

PMID: 9570540 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


40: Brain Pathol. 1998 Apr;8(2):263-76. 

Frequent inactivation of CDKN2A and rare mutation of TP53 in PCNSL.

Cobbers JM, Wolter M, Reifenberger J, Ring GU, Jessen F, An HX, Niederacher D,
Schmidt EE, Ichimura K, Floeth F, Kirsch L, Borchard F, Louis DN, Collins VP,
Reifenberger G.

Department of Neuropathology, Heinrich-Heine-Universitat, Dusseldorf, Germany.

Twenty primary central nervous system lymphomas (PCNSL) from immunocompetent
patients (nineteen B-cell lymphomas and one T-cell lymphoma) were investigated
for genetic alterations and/or expression of the genes BCL2, CCND1, CDK4,
CDKN1A, CDKN2A, MDM2, MYC, RB1, REL, and TP53. The gene found to be altered most
frequently was CDKN2A. Eight tumors (40%) showed homozygous and two tumors (10%)
hemizygous CDKN2A deletions. Furthermore, methylation analysis of six PCNSL
without homozygous CDKN2A loss revealed methylation of the CpG island within
exon 1 of CDKN2A in three instances. Reverse transcription PCR analysis of
CDKN2A mRNA expression was performed for 11 tumors and showed either no or weak
signals. Similarly, immunocytochemistry for the CDKN2A gene product (p16)
remained either completely negative or showed expression restricted to single
tumor cells. None of the PCNSL showed amplification of CDK4. Similarly,
investigation of CCND1 revealed no amplification, rearrangement or
overexpression. The retinoblastoma protein was strongly expressed in all tumors.
Only one PCNSL showed a mutation of the TP53 gene, i.e., a missense mutation at
codon 248 (CGG to TGG:Arg to Trp). No evidence of BCL2 gene rearrangement was
found in 11 tumors investigated. The bcl-2 protein, however, was strongly
expressed in most tumors. None of the 20 PCNSL demonstrated gene amplification
of MDM2, MYC or REL. In summary, inactivation of CDKN2A by either homozygous
deletion or DNA methylation represents an important molecular mechanism in
PCNSL. Mutation of the TP53 gene and alterations of the other genes investigated
appear to be of minor significance in these tumors.

PMID: 9546285 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


41: J Exp Med. 1998 Mar 2;187(5):663-74. 

B lymphocytes differentially use the Rel and nuclear factor kappaB1 (NF-kappaB1)
transcription factors to regulate cell cycle progression and apoptosis in
quiescent and mitogen-activated cells.

Grumont RJ, Rourke IJ, O'Reilly LA, Strasser A, Miyake K, Sha W, Gerondakis S.

The Walter and Eliza Hall Institute of Medical Research, Post Office The Royal
Melbourne Hospital, Victoria 3050, Australia.

Rel and nuclear factor (NF)-kappaB1, two members of the Rel/NF-kappaB
transcription factor family, are essential for mitogen-induced B cell
proliferation. Using mice with inactivated Rel or NF-kappaB1 genes, we show that
these transcription factors differentially regulate cell cycle progression and
apoptosis in B lymphocytes. Consistent with an increased rate of mature B cell
turnover in naive nfkb1-/- mice, the level of apoptosis in cultures of quiescent
nfkb1-/-, but not c-rel-/-, B cells is higher. The failure of c-rel-/- or
nfkb1-/- B cells to proliferate in response to particular mitogens coincides
with a cell cycle block early in G1 and elevated cell death. Expression of a
bcl-2 transgene prevents apoptosis in resting and activated c-rel-/- and
nfkb1-/- B cells, but does not overcome the block in cell cycle progression,
suggesting that the impaired proliferation is not simply a consequence of
apoptosis and that Rel/NF-kappaB proteins regulate cell survival and cell cycle
control through independent mechanisms. In contrast to certain B lymphoma cell
lines in which mitogen-induced cell death can result from
Rel/NF-kappaB-dependent downregulation of c-myc, expression of c-myc is normal
in resting and stimulated c-rel-/- B cells, indicating that target gene(s)
regulated by Rel that are important for preventing apoptosis may differ in
normal and immortalized B cells. Collectively, these results are the first to
demonstrate that in normal B cells, NF-kappaB1 regulates survival of cells in
G0, whereas mitogenic activation induced by distinct stimuli requires different
Rel/NF-kappaB factors to control cell cycle progression and prevent apoptosis.

PMID: 9480976 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


42: J Biol Chem. 1998 Jan 2;273(1):592-9. 

Discrimination between RelA and RelB transcriptional regulation by a dominant
negative mutant of IkappaBalpha.

Ferreira V, Tarantino N, Korner M.

Laboratoire d'Immunologie Cellulaire, CNRS URA 625, Bat. CERVI, Hopital de la
Pitie Salpetriere, 83, Bd. de l'Hopital, 75013 Paris, France.

RelA and RelB belong to the nuclear factor-kappaB (NF-kappaB-Rel) transcription
factor family. Both proteins are structurally and functionally related, but
their intracellular and tissue distributions are different. In resting cells,
RelB is found mostly in the nucleus, whereas RelA is sequestered in the cytosol
by protein inhibitors, among which IkappaBalpha is the dominant form in
lymphocytes. Upon cellular activation IkappaBalpha is proteolyzed, allowing RelA
dimers to enter the nucleus and activate target genes. To study the selectivity
of gene regulation by RelA and RelB, we generated T cell lines stably expressing
a dominant negative mutant of IkappaBalpha. We show that selective inhibition of
RelA-NF-kappaB decreased induction of NFKB1, interleukin-2, and
interleukin-2Ralpha genes but not c-myc. Transcription driven by the
IkappaBalpha promoter was blocked by the transgenic IkappaBalpha; however, wild
type IkappaBalpha was expressed in the transgenic cell clones but with much
slower kinetics than that in control cells. Wild type IkappaBalpha expression
was concomitant with RelB up-regulation, suggesting that RelB could be involved
in transcription of IkappaBalpha through binding to an alternative site. These
results indicate that RelB and RelA have both distinct and overlapping effects
on gene expression.

PMID: 9417120 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


43: Mol Cell Biol. 1997 Dec;17(12):7375-85. 

I kappaB alpha physically interacts with a cytoskeleton-associated protein
through its signal response domain.

Crepieux P, Kwon H, Leclerc N, Spencer W, Richard S, Lin R, Hiscott J.

Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research,
Department of Medicine, McGill University, Montreal, Que., Canada.

The I kappaB alpha protein is a key molecular target involved in the control of
NF-kappaB/Rel transcription factors during viral infection or inflammatory
reactions. This NF-kappaB-inhibitory factor is regulated by posttranslational
phosphorylation and ubiquitination of its amino-terminal signal response domain
that targets I kappaB alpha for rapid proteolysis by the 26S proteasome. In an
attempt to identify regulators of the I kappaB alpha inhibitory activity, we
undertook a yeast two-hybrid genetic screen, using the amino-terminal end of I
kappaB alpha as bait, and identified 12 independent interacting clones. Sequence
analysis identified some of these cDNA clones as Dlc-1, a sequence encoding a
small, 9-kDa human homolog of the outer-arm dynein light-chain protein. In the
two-hybrid assay, Dlc-1 also interacted with full-length I kappaB alpha protein
but not with N-terminal-deletion-containing versions of I kappaB alpha. I kappaB
alpha interacted in vitro with a glutathione S-transferase-Dlc-1 fusion protein,
and RelA(p65) did not displace this association, demonstrating that p65 and
Dlc-1 contact different protein motifs of I kappaB alpha. Importantly, in HeLa
and 293 cells, endogenous and transfected I kappaB alpha coimmunoprecipitated
with Myc-tagged or endogenous Dlc-1. Indirect immunofluorescence analyzed by
confocal microscopy indicated that Dlc-1 and I kappaB alpha colocalized with
both nuclear and cytoplasmic distribution. Furthermore, Dlc-1 and I kappaB alpha
were found to associate with the microtubule organizing center, a perinuclear
region from which microtubules radiate. Likewise, I kappaB alpha colocalized
with alpha-tubulin filaments. Taken together, these results highlight an
intriguing interaction between the I kappaB alpha protein and the human homolog
of a member of the dynein family of motor proteins and provide a potential link
between cytoskeleton dynamics and gene regulation.

PMID: 9372968 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


44: Cell Immunol. 1997 Oct 10;181(1):13-22. 

Role for CD40-mediated activation of c-Rel and maintenance of c-myc RNA levels
in mitigating anti-IgM-induced growth arrest.

Siebelt F, Berberich I, Shu G, Serfling E, Clark EA.

Department of Microbiology and Regional Primate Research Center, University of
Washington, Seattle, Washington, 98195, USA.

CD40 crosslinking on B cells activates NF-kappaB and stress-activated protein
kinase (SAPK) pathways. Since CD40 crosslinking rescues WEHI 231 B cells from
anti-IgM-induced apoptosis, those pathways were likely candidates to be
involved. Indeed, both signaling cascades predominated in anti-IgM-treated WEHI
231 cells, treated concurrently with anti-CD40 to rescue them from apoptosis.
Crosslinking of CD40 activated the NF-kappaB proteins c-Rel and p50, but had no
influence on their cytoplasmic steady state level. However, in contrast to-and
even in the presence of-anti-IgM-mediated signals, engagement of CD40 resulted
in a prolonged nuclear translocation of c-Rel, thereby allowing the formation of
active NF-kappaB complexes. Consistent with this, the upstream regulatory
element of the c-myc promoter, known to be regulated by NF-kappaB, was
differently regulated after BCR ligation vs BCR plus CD40 crosslinking. The
level of c-myc RNA was rapidly downregulated after BCR engagement, but
persistent in the presence of CD40 signaling. Copyright 1997 Academic Press.

PMID: 9344491 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


45: Prostaglandins. 1997 Aug;54(2):549-68. 

NSAID-induced apoptosis in Rous sarcoma virus-transformed chicken embryo
fibroblasts is dependent on v-src and c-myc and is inhibited by bcl-2.

Lu X, Fairbairn DW, Bradshaw WS, O'Neill KL, Ewert DL, Simmons DL.

Department of Zoology, Brigham Young University, Provo, UT 84602, USA.

Mounting epidemiological and experimental evidence implicates non-steroidal
antiinflammatory drugs as anti-tumorigenic agents. Our previous work showed that
nonsteroidal antiinflammatory drug treatment of src-transformed chicken embryo
fibroblasts caused apoptosis--a mechanism by which these drugs might exert their
anti-tumorigenic effect. The present studies employ a sensitive technique for
detecting single- and double-stranded DNA cleavage (the comet assay) to
quantitate apoptosis. By this method pp60v-src, which antagonizes apoptosis in
many cell systems, was found to induce apoptosis in 11-23% of serum-starved
fibroblasts. However, treatment with diclofenac following pp60v-src activation
produced a much stronger response beginning within 6 hours of treatment that
resulted in 100% lethality. During cell death, cyclooxygenase-2 but not
cyclooxygenase-1 mRNA was found to be uniformly increased by all apoptotic drugs
tested. Examination of the expression of apoptosis-associated genes showed that
c-rel and p53 (found in normal or v-src-transformed chicken embryo fibroblasts
at moderate levels), and bcl-2 (present at an extremely low level) were largely
unchanged by treatment with eight different nonsteroidal antiinflammatory drugs.
However, overexpression of human bcl-2 inhibited diclofenac-mediated apoptosis
by 90%, demonstrating directly that bcl-2 expression can regulate nonsteroidal
antiinflammatory drug induction of cell death. The proto-oncogene c-myc is known
to cause apoptosis in chicken embryo fibroblasts when artificially overexpressed
in cells deprived of trophic factors. We found that nonsteroidal
antiinflammatory drug treatment following pp60v-src activation persistently
induced myc protein and mRNA by more than 20-fold above that evoked by pp60v-src
activation alone. Moreover, transfection of antisense c-myc oligonucleotides
reduced drug-induced myc expression by 80% and caused a concomitant 50%
reduction in cell death. These findings suggest that nonsteroidal
antiinflammatory drug-induced apoptosis proceeds through a src/myc dependent
pathway which is negatively regulated by bcl-2.

PMID: 9380798 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


46: J Virol. 1997 Aug;71(8):5972-81. 

VBP and RelA regulate avian leukosis virus long terminal repeat-enhanced
transcription in B cells.

Curristin SM, Bird KJ, Tubbs RJ, Ruddell A.

Department of Microbiology and Immunology and Cancer Center, University of
Rochester, School of Medicine and Dentistry, New York 14642, USA.

The avian leukosis virus (ALV) long terminal repeat (LTR) contains a compact
transcription enhancer that is active in many cell types. A major feature of the
enhancer is multiple CCAAT/enhancer element motifs that could be important for
the strong transcriptional activity of this unit. The contributions of the three
CCAAT/enhancer elements to LTR function were examined in B cells, as this cell
type is targeted for ALV tumor induction following integration of LTR sequences
next to the c-myc proto-oncogene. One CCAAT/enhancer element, termed a3, was
found to be the most critical for LTR enhancement in transiently transfected B
lymphoma cells, while in chicken embryo fibroblasts all three elements
contributed equally to enhancement. Gel shift assays demonstrated that
vitellogenin gene-binding protein (VBP), a member of the PAR subfamily of C/EBP
factors, is a major component of the nuclear proteins binding to the a3
CCAAT/enhancer element. VBP activated transcription through the a3
CCAAT/enhancer element, supporting the idea that VBP is important for LTR
enhancement in B cells. A member of the Rel family of proteins was also
identified as a component of the a3 protein binding complex in B cells. Gel
shift and immunoprecipitation assays indicated that this factor is RelA. Gel
shift assays demonstrated that while RelA does not bind directly to the LTR
CCAAT/enhancer elements, it does interact with VBP to potentiate VBP DNA binding
activity. The synergistic interaction of VBP and RelA increased CCAAT/enhancer
element-mediated transcription, indicating that both factors may be important
for viral LTR regulation and also for expression of many cellular genes.

PMID: 9223487 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


47: Front Biosci. 1997 Feb 15;2:d49-60. 

Role of NF-kappaB in the control of apoptotic and proliferative responses in
IL-2-responsive T cells.

Gomez J, Garcia-Domingo D, Martinez-A C, Rebollo A.

Department of Immunology and Oncology, Centro Nacional de Biotecnologia, Campus
de Cantoblanco, E-28049 Madrid, Spain.

The NF-kappaB/Rel/IkappaB family of transcription factors regulates a number of
genes involved in a wide variety of biological processes. The activation of p53,
c-myc and Ras genes suggests a role for NF-kappaB in cell proliferation;
NF-kappaB is also important in immune and inflammatory responses. By virtue of
its role in apoptosis, NF-kappaB participates in the thymus as well as in
embryonic development. The NF-kappaB family of transcription factors is also
involved in viral transcription, transformation and in the development of some
types of human cancers. Given the pivotal role of NF-kappaB, clarification is
needed of the mechanisms through which its deregulation contributes to disease.
Several aspects of NF-kappaB regulation, such as phosphatase involvement, the
mechanism of IkappaB ubiquitination and the regulation of nuclear translocation,
remain obscure. Here, we review and discuss the function of NF-kappaB activation
in IL-2-stimulation and in apoptosis induced by IL-2 deprivation in T cells.

Publication Types:
    Review
    Review, Tutorial

PMID: 9159211 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


48: Mol Cell Biol. 1996 Sep;16(9):5015-25. 

Inhibition of c-myc expression induces apoptosis of WEHI 231 murine B cells.

Wu M, Arsura M, Bellas RE, FitzGerald MJ, Lee H, Schauer SL, Sherr DH,
Sonenshein GE.

Department of Biochemistry, Boston University School of Medicine, Massachusetts
02118, USA.

Treatment of WEHI 231 immature B-lymphoma cells with an antibody against their
surface immunoglobulin (anti-Ig) induces apoptosis and has been studied
extensively as a model of B-cell tolerance. Anti-Ig treatment of exponentially
growing WEHI 231 cells results in an early transient increase in c-myc
expression that is followed by a decline to below basal levels; this decrease in
c-myc expression immediately precedes the induction of cell death. Here we have
modulated NF-kappaB/Rel factor activity, which regulates the rate of c-myc gene
transcription, to determine whether the increase or decrease in c-Myc-levels
mediates apoptosis in WEHI 231 cells. Addition of the serine/threonine protease
inhibitor N-tosyl-L-phenylalanine chloromethyl ketone (TPCK), which blocks the
normally rapid turnover of the specific inhibitor of NF-kappaB/Rel IkappaBalpha
in these cells, caused a drop in Rel-related factor binding. TPCK treatment
resulted in decreased c-myc expression, preventing the usual increase seen
following anti-Ig treatment. Whereas inhibition of the induction of c-myc
expression mediated by anti-Ig failed to block apoptosis, reduction of c-myc
expression in exponentially growing WEHI 231 cells induced apoptosis even in the
absence of anti-Ig treatment. In WEHI 231 clones ectopically expressing c-Myc,
apoptosis induced by treatment with TPCK or anti-Ig was significantly diminished
and cells continued to proliferate. Furthermore, apoptosis of WEHI 231 cells
ensued following enhanced expression of Mad1, which has been found to reduce
functional c-Myc levels. These results indicate that the decline in c-myc
expression resulting from the drop in NF-kappaB/Rel binding leads to activation
of apoptosis of WEHI 231 B cells.

PMID: 8756660 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


49: Immunity. 1996 Jul;5(1):31-40. 

TGF beta 1 inhibits NF-kappa B/Rel activity inducing apoptosis of B cells:
transcriptional activation of I kappa B alpha.

Arsura M, Wu M, Sonenshein GE.

Department of Biochemistry, Boston University School of Medicine, Massachusetts
02118, USA.

TGF beta 1 treatment of B cell lymphomas decreases c-myc gene expression and
induces apoptosis. Since we have demonstrated NF-kappa/Rel factors play a key
role in transcriptional control of c-myc, we explored the effects of TGF beta1
on WEHI 231 immature B cells. A reduction in NF-kappa B/Rel activity followed
TGF beta 1 treatment. In WEHI 231 and CH33 cells, we observed an increase in I
kappa B alpha, a specific NF-kappa B/Rel inhibitor, due to transcriptional
induction. Engagement of surface CD40 or ectopic c-Rel led to maintenance of
NF-kappa B/Rel and c-Myc expression and protection of WEHI 231 cells from TGF
beta 1-mediated apoptosis. Ectopic c-Myc expression overrode apoptosis induced
by TGF beta 1. Thus, downmodulation of NF-kappa B/Rel reduces c-Myc expression,
which leads to apoptosis in these immature B cell models of clonal deletion. The
inhibition of NF-kappa B/Rel activity represents a novel TGF beta signaling
mechanism.

PMID: 8758892 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


50: J Immunol. 1996 Jul 1;157(1):81-6. 

Maintenance of nuclear factor-kappa B/Rel and c-myc expression during CD40
ligand rescue of WEHI 231 early B cells from receptor-mediated apoptosis through
modulation of I kappa B proteins.

Schauer SL, Wang Z, Sonenshein GE, Rothstein TL.

Department of Microbiology, Boston University Medical School, MA 02118, USA.

Engagement of surface IgM (sIgM) on WEHI 231 murine B lymphoma cells leads to
abortive activation and apoptosis, suggesting that this cell line may represent
a model for tolerance. Loss of viability in these cells is preceded by an early
increase in c-myc RNA levels followed by a decline below control values,
implicating c-myc in the control of apoptosis. Costimulation with CD40 ligand
(CD40L) has been shown to rescue WEHI 231 cells from anti-sIgM-induced
apoptosis, and therefore, the effects of CD40L on c-myc RNA and protein levels
were measured. Treatment of these cells with the combination of CD40L and
anti-sIgM led to induction and maintenance of elevated levels of c-myc RNA and
protein. Since transcriptional regulation of c-myc is mediated through two
nuclear factor-kappa B (NF-kappa B) sites in WEHI 231, the effects of CD40L on
DNA binding by this family of transcription factors were evaluated. CD40L
induced and sustained the levels of NF-kappa B binding to both of these sites,
paralleling the changes in c-myc RNA levels. Elevated levels of NF-kappa B were
partially achieved through a sustained decrease in the steady state amount of
the NF-kappa B/Rel-specific inhibitory protein, I kappa B alpha, and a transient
decrease in I kappa B beta. These data lend support to the hypothesis that
anti-sIgM-induced apoptosis is caused by a drop in c-myc expression and that an
appropriate second signal, such as that provided by CD40L, is able to rescue
these cells by inducing NF-kappa B and thereby maintaining c-myc RNA levels.

PMID: 8683159 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


51: Eur J Cancer B Oral Oncol. 1995 Nov;31B(6):384-91. 

Differential c-myc, c-jun, c-raf and p53 expression in squamous cell carcinoma
of the head and neck: implication in drug and radioresistance.

Riva C, Lavieille JP, Reyt E, Brambilla E, Lunardi J, Brambilla C.

Lung and Airways Cancer Research Group, Albert Bonniot Institute, La Tronche,
France.

The expression of oncogenes c-myc, c-jun and c-raf and tumour suppressor gene
p53 was assessed by northern blot analysis of 42 tumours and p53 protein
expression by immunohistochemistry on paraffin-embedded sections from 36
specimens of squamous cell carcinoma of the head and neck (SCCHN) obtained
before therapy. Of the 42 tumours, 89, 100 and 100% expressed c-myc, c-jun and
c-raf oncogenes, respectively. These oncogene expressions did not correlate with
sex, age or clinical stage of the disease. However, an association was found
between low c-myc expression (P = 0.0001) and high c-jun expression (P = 0.0001)
and absence of tumoral response to neoadjuvant chemotherapy. On the other hand,
c-raf overexpression was observed in patients resistant to radiation therapy (P
= 0.0494). Forty-two per cent of the tumours showed p53 protein overexpression,
which did not correlate with any clinical parameter. This p53 protein
overexpression was associated with high p53 mRNA levels (REL) (P = 0.0223). A
correlation was found between increased c-myc RNA expression and lack of p53
protein expression (P = 0.0407). In addition, a lack of p53 protein expression
was indicative of tumour relapse (P = 0.05). None of these biological parameters
were associated with disease-free survival (Cox-Mantel test). In conclusion, the
overexpression of c-myc, c-jun and c-raf may be independently associated to
tumoral response to chemotherapy or radiotherapy, or to tumour relapse, but fail
to predict long-term survival.

PMID: 8746269 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


52: Int J Cancer. 1995 May 29;61(5):698-705. 

Erratum in:
    Int J Cancer 1995 Nov 15;63(4):609.

Quantitative variation of proto-oncogene and cytokine gene expression in
isolated breast fibroblasts.

Spanakis E, Brouty-Boye D.

Institut d'Oncologie Cellulaire et Moleculaire Humaine, Bobigny, France.

Transcripts coding for transcription factors (RB, P53, FOS, MYC, MYB, ERBA,
REL), growth factors (FGF1, FGF2, INT2, TGFA, TGFB, PDGF, IGF1, IGF2),
interleukins, (IL1, IL2, IL3, IL4, IL6, TNF), growth-factor receptors or
cytosolic protein kinases (RAF, PIM, FES, MET, SRC, ROS, TRK, KIT, CSFR, IGFR,
PDGFR, EGFR, NEU) were quantified in cultured human mammary fibroblasts from
normal tissues, benign tumours, carcinomas and post-radiation fibrosis lesions
by slot-blot autoradiography and image analysis. The effects of a
differentiating agent (cholera toxin) and of a tumour promoter
(12-O-tetradecanoyl-phorbol-13-acetate) were also examined. The drugs modulated
the levels of the anti-oncogene transcripts (RB, P53) and of ERBA, REL, RAF,
MET, ROS, TRK, CSFR, EGFR, NEU, FGF1, INT2, IGF1, IL1, IL2, IL4 and IL6. Apart
from this variation, there were multiple differences in gene expression among
normal and pathological cells (concerning all but P53, TGFB and interleukin
transcripts) and between sub-types defined by the presence of alpha-sm-actin
(myofibroblasts) or EDB-fibronectin (RAF, ROS, FES, KIT, IGFR, NEU, INT2, TGFB,
PDGF, IGFs, ILs). It appears, therefore, that mammary stroma progress
irreversibly along with the epithelium during tumoral development, and that
breast cancer is not only a multi-gene but also a multi-tissue phenotype.

PMID: 7768644 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


53: Oncogene. 1995 Mar 2;10(5):857-68. 

The v-Rel oncoprotein blocks apoptosis and proteolysis of I kappa B-alpha in
transformed chicken spleen cells.

White DW, Roy A, Gilmore TD.

Department of Biology, Boston University, Massachusetts 02215-2406.

The v-Rel oncoprotein of the avian Rev-T retrovirus malignantly transforms
chicken spleen cells in vivo and in vitro. We previously described two
temperature-sensitive (ts) mutants of v-Rel (v-G37E and v-R273H) that show a ts
ability to transform chicken spleen cells and to bind to DNA in vitro. We now
show that spleen cell lines transformed by ts v-Rel proteins at the permissive
temperature undergo apoptosis when cells are shifted to the nonpermissive
temperature. The levels of most proteins (including v-Rel, p53, c-Myc, Rb and
Bcl-2) do not change in these cells even at advanced stages of apoptosis.
However, the chicken I kappa B-alpha protein (also called p40), which is in a
complex with v-Rel in transformed cells, is degraded when ts v-Rel-transformed
cells are shifted to the nonpermissive temperature. In v-R273H-transformed
cells, p40 is degraded without the appearance of proteolytic intermediates. In
contrast, in v-G37E-transformed cells, p40 is cleaved to an intermediate species
that is missing approximately 3-4 kDa from its amino terminus. This truncated
form of p40 is found in a detergent-insoluble fraction and can also be detected
in wild-type v-Rel-transformed cells that are induced to undergo apoptosis by
treatment with cycloheximide. Both ts v-Rel proteins are ts for interaction with
p40 in vitro. The results reported here indicate that v-Rel blocks a normal
pathway of programmed cell death and that I kappa B-alpha can undergo multiple
degradative pathways, which can be induced by alterations in the structure of
the Rel protein to which it is bound.

PMID: 7898928 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


54: J Exp Med. 1995 Mar 1;181(3):1169-77. 

Role of Rel-related factors in control of c-myc gene transcription in
receptor-mediated apoptosis of the murine B cell WEHI 231 line.

Lee H, Arsura M, Wu M, Duyao M, Buckler AJ, Sonenshein GE.

Department of Biochemistry, Boston University Medical School, Massachusetts
02118.

Treatment of immature murine B lymphocytes with an antiserum against their
surface immunoglobulin (sIg)M results in cell death via apoptosis. The WEHI 231
B cell line (IgM, kappa) has been used extensively as a model for this anti-Ig
receptor-mediated apoptosis. Anti-sIg treatment of WEHI 231 cells causes an
early, transient increase in the levels of c-myc messenger RNA and gene
transcription, followed by a rapid decline below control values. Given the
evidence for a role of the c-myc gene in promoting apoptosis, we have
characterized the nature and kinetics of changes in the binding of Rel-related
factors, which modulate c-myc promoter activity. In exponentially growing WEHI
231 cells, multiple Rel-related binding activities were detectable. The major
binding species was identified as p50/c-Rel heterodimers; only minor amounts of
nuclear factor kappa B (NF-kappa B) (p50/p65) were detectable. Cotransfection of
an inhibitor of NF-kappa B (I kappa B)-alpha expression vector reduced
c-myc-promoter/upstream/exon1-CAT reporter construct activity, indicating the
role of Rel factor binding in c-myc basal expression in these cells. Treatment
with anti-sIg resulted in a rapid transient increase in the rate of c-myc gene
transcription and in the binding of Rel factors. At later times, formation of
p50 homodimer complexes occurred. In cotransfection analysis, p65 and c-Rel
expression potently and modestly transactivated the c-myc promoter,
respectively, whereas, overexpression of the p50 subunit caused a significant
drop in its activity. The role of activation of Rel-family binding was
demonstrated directly upon addition of the antioxidant
pyrrolidinedithiocarbamate, which inhibited the anti-sIg-mediated activation of
the endogenous c-myc gene. Similarly, induction after anti-sIg treatment of a
transfected c-myc promoter was abrogated upon cotransfection of an I kappa
B-alpha expression vector. These results implicate the Rel-family in Ig
receptor-mediated signals controlling the activation of c-myc gene transcription
in WEHI 231 cells, and suggest a role for this family in apoptosis of this line,
which is mediated through a c-myc signaling pathway.

PMID: 7869034 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


55: Mol Cell Biol. 1995 Mar;15(3):1806-16. 

v-rel Induces ectopic expression of an adhesion molecule, DM-GRASP, during
B-lymphoma development.

Zhang G, Slaughter C, Humphries EH.

Mary Babb Randolph Cancer Center, West Virginia University, Morgantown
26506-9177.

In an effort to identify aberrantly expressed genes in v-rel-induced tumors,
monoclonal antibodies were developed that reacted selectively with avian B-cell
tumors. One antibody, HY78, immunoprecipitated a 120-kDa glycoprotein (p120)
from cells that express v-rel. N-terminal amino acid sequencing of p120
identified a 27-amino-acid sequence that is also present in DM-GRASP, an
adhesion molecule belonging to the immunoglobulin superfamily. Evidence from
tissue distribution, immunological cross-reaction, PCR amplification, cDNA
cloning, and DNA sequence shows that p120 is indeed DM-GRASP. Northern (RNA)
analysis using a probe from the DM-GRASP gene identified a 5.3-kb transcript in
mRNA from bursa, thymus, and brain as well as from v-rel-induced B-cell
lymphomas but not from bursal B cells. The induction of this protein by v-rel
during the development of bursal B-cell lymphomas appears, therefore, to be
ectopic in nature. Overexpression of v-rel or c-rel in chicken embryonic
fibroblasts, B-cell lines, and spleen mononuclear cells induces the expression
of DM-GRASP. The ratio of DM-GRASP to v-Rel was fivefold higher than that of
DM-GRASP/c-Rel in a B-cell line, DT95. Interestingly, the presence of HY78
antibody inhibits the in vitro proliferation of v-rel-transformed cells but not
cells that immortalized by myc. These data suggest that DM-GRASP is one of the
genes induced during v-rel-mediated tumor development and that DM-GRASP may be
involved in the growth of v-rel tumor cells.

PMID: 7862170 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


56: Curr Top Microbiol Immunol. 1995;194:247-55. 

Role of the Rel-family of transcription factors in the regulation of c-myc gene
transcription and apoptosis of WEHI 231 murine B-cells.

Lee H, Wu M, La Rosa FA, Duyao MP, Buckler AJ, Sonenshein GE.

Department of Biochemistry, Boston University Medical School, MA 02118.

PMID: 7895496 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


57: Mol Cell Biol. 1994 Dec;14(12):7967-74. 

NF-kappa B sites function as positive regulators of expression of the
translocated c-myc allele in Burkitt's lymphoma.

Ji L, Arcinas M, Boxer LM.

Center for Molecular Biology in Medicine, Palo Alto Veterans Administration
Hospital, California.

An in vivo footprint over a potential NF-kappa B site in the first exon of the
c-myc gene has been identified on the translocated allele in the Ramos Burkitt's
lymphoma cell line. The potential NF-kappa B site in the 5' flanking sequence of
c-myc was found to be occupied on the translocated allele in the Raji Burkitt's
cell line. Electrophoretic mobility shift assays with each of these sequences
demonstrated complexes with mobilities identical to those of the NF-kappa B site
from the kappa light-chain gene. A supershift was obtained with anti-p50
antibody with the exon site. The upstream-site shift complex disappeared with
the addition of anti-p50 antibody. Binding of NF-kappa B proteins to the c-myc
exon and upstream sites was demonstrated by induction of binding upon
differentiation of pre-B 70Z/3 cells to B cells. UV cross-linking experiments
revealed that a protein with a molecular mass of 50 kDa bound to the exon and
upstream sites. Transfection experiments with Raji cells demonstrated that both
sites functioned as positive regulatory regions, with a drop in activity level
when either site was mutated. Access to these sites is blocked in the silent
normal c-myc allele in Burkitt's lymphoma cells, while Rel family proteins bind
to these sites in the translocated allele. We conclude that the two NF-kappa B
sites function as positive regulatory regions for the translocated c-myc gene in
Burkitt's lymphoma.

PMID: 7969136 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


58: Mol Cell Biol. 1994 Aug;14(8):5349-59. 

Sequential induction of NF-kappa B/Rel family proteins during B-cell terminal
differentiation.

Liou HC, Sha WC, Scott ML, Baltimore D.

Rockfeller University, New York, New York 10021.

The NF-kappa B/Rel family of at least five transcription factor polypeptides is
thought to function both as a developmental regulator in B cells and as a rapid
response system in all cells. To examine this notion in more detail, we
determined the protein contents of both the inducible and constitutive NF-kappa
B/Rel activities in a pre-B-cell line, 70Z/3, and a mature B-cell line, WEHI
231. NF-kappa B p50/p65 is the major inducible nuclear complex after
lipopolysaccharide or phorbol myristate acetate treatment of 70Z/3 cells. The
constitutive and inducible complexes in WEHI 231 cells are mainly composed of
p50 and Rel. The constitutive or induced activities are all sensitive to I kappa
B-alpha, but this inhibitor is very short-lived in WEHI 231 cells, suggesting
that the balance between synthesis and degradation of I kappa B-alpha determines
whether a particular cell lineage has constitutive activity. A patterned
expression of the NF-kappa B/Rel activator proteins emerges from an analysis of
other B-lineage cell lines and splenic B cells: mainly p50 and p65 in pre-B (and
non-B) cells, a predominance of Rel and p50 in mature B cells, and expression of
p52 and RelB in plasmacytoma lines. This ordered pattern of regulators may
reflect the requirement for expression of different genes during terminal B-cell
differentiation because different combinations of NF-kappa B/Rel family members
preferentially activate distinct kappa B sites in reporter constructs.

PMID: 8035813 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


59: Mol Cell Biol. 1994 Feb;14(2):1039-44. 

Differential regulation of the c-myc oncogene promoter by the NF-kappa B rel
family of transcription factors.

La Rosa FA, Pierce JW, Sonenshein GE.

Department of Biochemistry, Boston University School of Medicine, Massachusetts
02118-2394.

The murine c-myc gene contains two elements responsive to the
rel-oncogene-related family of NF-kappa B factors. Previously we have shown that
factor binding to these two NF-kappa B elements mediates induction of
transcription of the c-myc promoter upon interleukin-1 treatment of human dermal
fibroblasts and human T-cell leukemia virus type I tax gene expression in T
cells (D. J. Kessler, M. P. Duyao, D. B. Spicer, and G. E. Sonenshein, J. Exp.
Med. 176:787-792, 1992; M. P. Duyao, D. J. Kessler, D. B. Spicer, C.
Bartholomew, J. L. Cleveland, M. Siekevitz, and G. E. Sonenshein, J. Biol. Chem.
267:16288-16291, 1992). To begin to delineate the specific roles of the
individual members of the NF-kappa B family, here we have tested their effects
on activation of a c-myc promoter/exon 1-CAT construct in NIH 3T3 cells.
Classical NF-kappa B (p65/p50) was a potent transcriptional activator of the
c-myc promoter. Cotransfection with either p65 alone or p65 in combination with
p50 mediated significant induction. In contrast, expression of either v-rel or
chicken c-rel failed to transactivate, while murine c-rel induced c-myc promoter
activity only slightly. Furthermore, induction by classical NF-kappa B was
inhibited by coexpression of either v-rel or chicken c-rel. Thus, individual
members of the rel family have differential effects of the c-myc promoter, which
can modulate overall transcriptional activity and allow for precise regulation
of this oncogene under diverse physiologic conditions.

PMID: 8289784 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


60: Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6140-4. 

The protooncogene c-sea encodes a transmembrane protein-tyrosine kinase related
to the Met/hepatocyte growth factor/scatter factor receptor.

Huff JL, Jelinek MA, Borgman CA, Lansing TJ, Parsons JT.

Department of Microbiology, University of Virginia, Charlottesville 22908.

c-sea is the cellular homologue of the avian erythroblastosis virus S13-encoded
oncogene v-sea. We have isolated and determined the nucleotide sequence of
overlapping chicken cDNAs that encode the putative c-sea protooncogene product.
The predicted reading frame encoded a 1404-aa polypeptide that had the structure
of a receptor-like protein-tyrosine kinase and exhibited the highest degree of
sequence similarity with the Met/hepatocyte growth factor/scatter factor
receptor. Analysis of steady-state RNA expression revealed that c-sea mRNA
levels were elevated approximately 5-fold in chicken embryo cells transformed by
activated variants of the src nonreceptor protein-tyrosine kinase gene but not
in cells transformed by the nuclear oncogenes v-myc or v-rel. A survey of c-sea
expression in a variety of chicken tissues indicated that the highest levels of
mRNA were located in peripheral white blood cell populations and in the
intestine.

PMID: 8392188 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


61: Eur J Biochem. 1993 Jan 15;211(1-2):7-18. 

Erratum in:
    Eur J Biochem 1993 Aug 1;215(3):907.

The Ets family of transcription factors.

Wasylyk B, Hahn SL, Giovane A.

CNRS-LGME/INSERM-U. 184, Institut de Chimie Biologique, Faculte de Medecine,
Strasbourg, France.

Interest in the Ets proteins has grown enormously over the last decade. The
v-ets oncogene was originally discovered as part of a fusion protein expressed
by a transforming retrovirus (avian E26), and later shown to be transduced from
a cellular gene. About 30 related proteins have now been found in species
ranging from flies to humans, that resemble the vEts protein in the so-called
'ets domain'. The ets domain has been shown to be a DNA-binding domain, that
specifically interacts with sequences containing the common core trinucleotide
GGA. Furthermore, it is involved in protein-protein interactions with co-factors
that help determine its biological activity. Many of the Ets-related proteins
have been shown to be transcription activators, like other nuclear oncoproteins
and anti-oncoproteins (Jun, Fos, Myb, Myc, Rel, p53, etc.). However, Ets-like
proteins may have other functions, such as in DNA replication and a general role
in transcription activation. Ets proteins have been implicated in regulation of
gene expression during a variety of biological processes, including growth
control, transformation, T-cell activation, and developmental programs in many
organisms. Signals regulating cell growth are transmitted from outside the cell
to the nucleus by growth factors and their receptors. G-proteins, kinases and
transcription factors. We will discuss how several Ets-related proteins fit into
this scheme, and how their activity is regulated both post- and
pre-translationally. Loss of normal control is often associated with conversion
to an oncoprotein. vEts has been shown to have different properties from its
progenitor, which might explain how it has become oncogenic. Oncogene-related
products have been implicated in the control of various developmental processes.
Evidence is accumulating for a role for Ets family members in Drosophila
development, Xenopus oocyte maturation, lymphocyte differentiation, and viral
infectious cycles. An ultimate hope in studying transformation by oncoproteins
is to understand how cells become cancerous in humans, which would lead to more
effective treatments. vEts induces erythroblastosis in chicken. Cellular
Ets-family proteins can be activated by proviral insertion in mice and, most
interestingly, by chromosome translocation in humans. We are at the beginning of
understanding the multiple facets of regulation of Ets activity. Future work on
the Ets family promises to provide important insights into both normal control
of growth and differentiation, and deregulation in illness.

Publication Types:
    Review

PMID: 8425553 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


62: J Virol. 1992 Jan;66(1):512-23. 

Activation of the c-myb locus is insufficient for the rapid induction of
disseminated avian B-cell lymphoma.

Pizer ES, Baba TW, Humphries EH.

Department of Microbiology, Southwestern Medical School, Dallas, Texas 75235.

We have previously reported that infection of 9- to 13-day-old chicken embryos
with RAV-1 results in rapid development of a novel B-cell lymphoma in which
proviral insertion has activated expression of the c-myb gene (E. Pizer and E.
H. Humphries, J. Virol. 63:1630-1640, 1989). The biological properties of these
B-cell lymphomas are distinct from those associated with the B-cell lymphomas
that develop following avian leukosis virus proviral insertion within the c-myc
locus. In an extension of this study, more than 200 chickens, infected as 10- to
11-day-old embryos, were examined for development of lymphomas that possess
disrupted c-myb loci. Fourteen percent developed disseminated B-cell lymphoma.
In the majority of these tumors, the RAV-1 provirus had inserted between the
first and second exons that code for p75c-myb. However, insertions between the
second and third exons and between the third and fourth exons were also
detected. In situ analysis of myb protein expression in tumor tissue revealed
morphological features suggesting that the tumor originates in the bursa. Within
the bursa, the lymphoma appeared to spread from follicle to follicle without
compromising the structural integrity of the organ. Tumor masses in liver
demonstrated heterogeneous levels of myb protein suggestive of biologically
distinct subpopulations. In contrast to the morbidity data, immunohistological
analysis of bursae from 4- to 6-week-old chickens at risk of developing
lymphomas bearing altered c-myb loci revealed lesions expressing elevated levels
of myb in 16 of 19 birds. The activated myb lymphoma displayed very poor
capacity to proliferate outside its original host. Only 1 of 33 in vivo
transfers of tumor to recipient hosts established a transplantable tumor. None
of the primary tumor tissue nor the transplantable tumor exhibited the capacity
for in vitro proliferation. Similar experimental manipulation has yielded in
vitro lines established from avian B-cell lymphomas expressing elevated levels
of c-myc or v-rel. The dependence on embryonic infection for development of
activated-myb lymphoma suggests a requirement for a specific target cell in
which c-myb is activated by proviral insertion. It is likely, moreover, that
continued tumor development requires elevated expression of myb proteins within
a specific cell population in a restricted stage of differentiation.

PMID: 1309260 [PubMed - indexed for MEDLINE]


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63: Oncogene. 1991 Aug;6(8):1409-15. 

Proto-oncogene expression in avian hematopoietic tissues.

Schuur ER, Baluda MA.

Department of Pathology, UCLA School of Medicine 90024.

Previous findings from this laboratory (Kim & Baluda, 1988) have shown that the
proto-oncogenes ETS, FPS, MHT (RAF), MYC and REL are expressed in avian
myeloblastosis virus (AMV)-transformed cells, whereas the MYB gene is repressed.
In this study five different chicken hematopoietic tissues which contained
varying concentrations of target cells for AMV transformation were analyzed to
determine whether the expression of these proto-oncogenes resulted from, or was
altered by, v-myb-induced leukemogenesis. Poly-A+ RNA from hematopoietic cells
of 11-13 day yolk sac, 16 day embryonic spleen, 1 day post-hatch bursa of
Fabricius, bone marrow and thymus, as well as from chicken embryonic fibroblasts
(CEF) was examined by Northern blot analysis. All five proto-oncogenes were
found to be expressed in the normal hematopoietic tissues. The ETS, MHT (RAF),
MYC, and REL genes, but not FPS, were expressed in CEF. The expression of these
five proto-oncogenes was not quantitatively or qualitatively altered in
AMV-transformed myeloid cells as compared with their normal counterparts. While
their expression is part of the hematopoietic phenotype of the target cells and
as such is necessary for susceptibility to AMV transformation, it is not
sufficient because thymocytes with a high level of expression are not
transformed. This is in contrast to MYB expression, which is totally repressed
in leukemic cells but probably not as a result of v-myb expression.

PMID: 1886713 [PubMed - indexed for MEDLINE]


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64: Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5857-61. 

Induction of apoptosis during normal and neoplastic B-cell development in the
bursa of Fabricius.

Neiman PE, Thomas SJ, Loring G.

Fred Hutchinson Cancer Research Center, University of Washington, Seattle 98104.

The lymphoid cells of embryonic bursal follicles are engaged in rapid growth and
preimmune diversification of immunoglobulin genes. Disruption of follicular
architecture by mechanical dispersion of these cells in short-term tissue
culture was accompanied by continued cell division and extensive cell death by
apoptosis. Apoptosis was suppressed in parallel cultures of intact follicles.
gamma Radiation also triggered extensive apoptosis in embryonic bursal follicles
within a few hours. Preneoplastic bursal stem cell populations induced by a
v-myc oncogene were hypersensitive to induction of apoptosis by follicular
dispersion and radiation. In contrast, tumor progression in v-myc- and
v-rel-initiated bursal neoplasms was accompanied by development of resistance to
induction of apoptosis. A programmed cell death pathway can be activated during
normal B-cell development in the bursa, and alterations in the expression of
this pathway accompany neoplastic change in this system.

PMID: 2062863 [PubMed - indexed for MEDLINE]


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65: Mol Cell Biol. 1990 Sep;10(9):4788-94. 

Characterization of a novel promoter insertion in the c-rel locus.

Kabrun N, Bumstead N, Hayman MJ, Enrietto PJ.

Department of Microbiology, State University of New York, Stony Brook 11794.

Avian leukosis virus (ALV)-induced neoplasias are commonly found associated with
integrations of proviral DNA in proximity to the myc gene. However, studies
suggest that other genetic events are necessary for the complete neoplastic
phenotype. A cell line (HP46) derived from an ALV-induced tumor has been
analyzed and found to contain, in addition to an alteration in the myc gene, a
promoter insertion in the c-rel locus. Both loci expressed large amounts of mRNA
coding for their respective proteins. Several rel-related transcripts were
expressed in the HP46 line, and four rel-related proteins of lower molecular
weight than the wild-type p68c-rel product were detected. At least two of these
transcripts contained U5 long terminal repeat sequences on the 5' end of the
RNA. Structural data suggest that the messages may have evolved by an
alternative splicing mechanism. This is the first example of a promoter
insertion in the c-rel locus, a gene whose viral counterpart v-rel is
responsible for the induction of lymphoid tumors.

PMID: 2167440 [PubMed - indexed for MEDLINE]


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66: Oncogene. 1989 Jul;4(7):845-52. 

Expression of the c-rel and c-myc proto-oncogenes in avian tissues.

Moore BE, Bose HR Jr.

Department of Microbiology, University of Texas, Austin 78712.

Reticuloendotheliosis virus (REV-T) transforms very immature avian lymphoid
cells and induces a rapidly fatal lymphoma. The viral oncogene, v-rel, encodes a
59 kDa phosphoprotein which is complexed with cellular proteins in the cytosol
of REV-T transformed lymphoid cell lines. The proto-oncogene, c-rel, has been
highly conserved among both vertebrate and invertebrate species. The expression
of both the c-rel and c-myc protoncogenes was characterized during avian
development. Two distinct rel-related transcripts were detected. A 4.0kb mRNA
was the principal transcript expressed in cells of hematopoietic origin with
highest levels detected in bursa, thymus, and spleen tissue obtained from
hatched birds. Relatively low levels of this 4.0 kb transcript were detected in
nonhematopoietic tissues. Thus, the distribution of this mRNA correlated with
the presence of target cells for transformation by v-rel. The 4.0 kb c-rel
transcript had a half-life of nearly 2 h in an avian lymphoid cell line. A
second rel-related transcript was identified in the ovary of young hens and
appeared to be expressed either in primary oocytes or in the developing
follicle. This 2.6 kb c-rel mRNA was detected at substantially lower levels in
cells of hematopoietic origin. Using radiolabeled RNA probes, the 2.6 kb c-rel
transcript was not detected in liver, brain, testes, or muscle. The c-myc
proto-oncogene was also expressed in cells of hematopoietic tissue and ova
obtained from hatched birds. While intermediate RNA levels were observed in
muscle and liver cells, the c-myc gene was not expressed in avian testes.

PMID: 2666905 [PubMed - indexed for MEDLINE]


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67: Eur J Immunol. 1988 Nov;18(11):1847-50. 

Transcription of protooncogenes during stimulation of normal human B
lymphocytes.

Smeland EB, Blomhoff HK, Ohlsson R, De Lange Davies C, Funderud S, Boye E.

Department of Pathology, Norwegian Radium Hospital, Oslo, Norway.

Protooncogenes play important roles in the regulation of growth and
differentiation of normal cells. In this study we have examined the cell
cycle-dependent regulation of transcription of various protooncogenes after
stimulation of human peripheral blood B lymphocytes. The transcriptional rate of
various genes was determined by means of a nuclear run-on assay. We found that
several protooncogenes were transcriptionally activated after stimulation (myc,
p53, K-ras, H-ras, sis and ets), but with different kinetics of induction. In
contrast, some oncogenes, especially those encoding membrane-associated or
cytoplasmatic proteins like abl, rel or mil/raf, were transcribed at a
relatively constant rate during the cell cycle.

PMID: 3060364 [PubMed - indexed for MEDLINE]


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68: Oncogene Res. 1988 Sep;3(2):147-54. 

Proto-oncogene expression in chicken leukemic cells induced by avian
myeloblastosis virus.

Kim WK, Baluda MA.

Department of Pathology, School of Medicine, University of California, Los
Angeles 90024.

Sixteen proto-oncogenes which have generated retroviral oncogenes were tested
for their expression in chicken leukemic cells induced by avian myeloblastosis
virus (AMV) and five were found to be expressed (c-ets, c-fps, c-mht, c-myc, and
c-rel). The size of the c-fps transcript (4.0 kb) was not in good agreement with
the size (approximately 3.0 kb) previously reported but was uniform in the
leukemic cells from 10 different chickens. The size of the other proto-oncogene
transcripts appeared normal. The five expressed proto-oncogenes represent
cellular genes involved in hematopoiesis. Interestingly the c-myb gene was not
expressed in any of the leukemic cells despite its expression in the immature
myeloid cells which are targets for AMV transformation. This could represent
down regulation of c-myb by v-myb or a differentiation-related arrest of c-myb
expression. The leukemic phenotype induced by v-myb may therefore become
expressed at a stage of myeloid differentiation when c-myb expression is
repressed.

PMID: 3226723 [PubMed - indexed for MEDLINE]


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69: Mol Endocrinol. 1988 Sep;2(9):816-24. 

Estrogen induces expression of c-fos and c-myc protooncogenes in rat uterus.

Weisz A, Bresciani F.

Istituto di Patologia Generale e Oncologia, Prima Facolta di Medicina e
Chirurgia, Universita di Napoli, Italy.

Estrogen stimulates DNA synthesis and cell proliferation in the luminal and
glandular epithelia of rodent uterus. We tested the hypothesis that the
mitogenic effect of estrogen occurs via activation of the expression of cellular
proto-oncogenes by measuring the rate of transcription of 20 proto-oncogenes
(abl, bas, erb-A, erb-B, ets, fms, fos, fps/fes, mos, myb, myc, N-myc, raf,
Ha-ras, Ki-ras, N-ras, rel, sis, src, and B-lym) in the uterus of ovariectomized
rats before and after injection of estrogen. c-onc transcriptional activity was
monitored both by an in vitro transcription assay on isolated nuclei (run-on)
and by analysis of mature mRNA. c-fos and c-myc proto-oncogenes were found to
respond to estrogen with increased expression: c-fos within 30 min, with a
first, sharp peak at 2 h and c-myc within 1.5 h, with a first, broad peak at 4-6
h. DNA synthesis start to increase in the uterus 13 h after estrogen injection
and show a first peak at 24 h. In the liver and muscle of the same animals there
is neither elevation of c-fos and c-myc expression nor increase of DNA
synthesis. The kinetics of the induction by estrogen of c-fos gene expression in
the uterus parallels the rate of formation of active nuclear estrogen-receptor
complex. Furthermore, the ability of estrogen to induce c-fos mRNA was not
abolished by the protein synthesis inhibitor cycloheximide.(ABSTRACT TRUNCATED
AT 250 WORDS)

PMID: 3173352 [PubMed - indexed for MEDLINE]


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70: Cancer Lett. 1988 Aug 15;41(2):147-55. 

Differential expression of cellular oncogenes during rat liver development.

Zhang XK, Wang Z, Lee A, Huang DP, Chiu JF.

Department of Biochemistry, College of Medicine, University of Vermont,
Burlington 05405.

The expression of a number of proto-oncogenes (myc, erb B, Ha-ras, bas, rel,
mos, sis, myb, ki-ras, fms, src and fos) was studied in developing rat liver.
Northern blot hybridization shows that cellular counterpart of erb B, Ha-ras,
and fos oncogenes were in an early stage of liver development, and the
expressions of these proto-oncogenes gradually decreased as the liver developed,
while c-myc transcript was found only in the rat fetal liver. The transcripts of
these oncogenes were found in high level in Morris hepatoma 7777. Bas
proto-oncogene was found in high expression at early stages of rat liver
development but was not in hepatoma 7777. The expression of other
proto-oncogenes studied (src, fm, rel, mos, sis, myb and ki-ras) did not change
significantly during liver development and was almost the same in hepatoma and
normal adult liver. Southern blot analysis demonstrates that gene amplification
and apparent gene rearrangement were not responsible for the change in
expression of erb B, Ha-ras, myc and fos proto-oncogenes. Our study gives
further evidence that erb B, myc, Ha-ras and fos proto-oncogenes are involved in
the control of cell growth and in the process of rat hepatocarcinogenesis.

PMID: 2456853 [PubMed - indexed for MEDLINE]


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71: Zhonghua Min Guo Wei Sheng Wu Ji Mian Yi Xue Za Zhi. 1988 Aug;21(3):141-50. 

Expression of oncogenes in human hepatoma cell lines.

Ting LP, Jeng KS, Chou CK, Su TS, Hu CP, Wong FH, Chang HK, Chang CM.

Graduate Institute of Microbiology and Immunology, National Yang-Ming Medical
College, Taipei, Taiwan, ROC.

The expression of 20 known cellular proto-oncogenes in human well-differentiated
hepatoma cell line Hep3B and poorly-differentiated hepatoma cell line HA22T/VGH
was studied by Northern blot hybridization. Among the cellular proto-oncogenes
examined, both cell lines express protein kinase genes including fps, mos and
raf; PDGF B chain sis gene; GTP/GDP binding protein gene Ha-ras and nuclear
protein genes including fos and myc. The expression of yes, abl, ros, src,
erb-B, erb-A, fms, Ki-ras, myb, rel and bas genes was not detected in both cell
lines.

PMID: 2854043 [PubMed - indexed for MEDLINE]


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72: Cancer Res. 1988 Jul 15;48(14):3972-6. 

Erratum in:
    Cancer Res 1988 Sep 1;48(17):5056.

Protooncogene expression in normal, preleukemic, and leukemic murine erythroid
cells and its relationship to differentiation and proliferation.

Robert-Lezenes J, Meneceur P, Ray D, Moreau-Gachelin F.

INSERM U-248, Faculte de Medecine Lariboisiere Saint-Louis, Paris, France.

The expression of 18 protooncogenes was examined by Northern blot analysis in
preleukemic and leukemic stages of murine erythroleukemias induced by Friend
viruses. As controls, erythropoietically stimulated spleens from
phenylhydrazine-treated mice were studied. Expression of 10 protooncogenes
(c-erb-A, c-erb-B, c-ets, c-sis, c-mos, c-rel, c-src, c-fes, c-fms, N-myc
[corrected] was not detectable in Friend erythroleukemias. One protooncogene
(c-src) was found expressed in normal erythroid cells but not in
erythroleukemias. Four protooncogenes (c-fos, c-abl, N-ras, and c-raf) were
expressed at low levels in both steps of erythroleukemia. c-fos and c-abl RNAs
were barely detectable in normal erythroid cells. High levels of four
protooncogene transcripts (c-H-ras, c-K-ras, c-myc, and c-myb) were detected in
preleukemic and leukemic tissues. While c-H-ras RNA was found at similar levels
in normal and leukemic erythroid cells, c-myc, c-myb, and c-K-ras were not
expressed in normal erythroid cells. To determine whether the elevated levels of
c-myc, c-myb, and c-K-ras RNAs in erythroleukemic cells are related to the
proliferative state or the undifferentiated state of the cells, the effect of
dimethyl sulfoxide-induced differentiation on oncogene expression in two
erythroleukemia cell lines was examined. Terminal differentiation was associated
with lack of c-myb expression while c-myc and c-K-ras expression was essentially
unaffected. These results suggest that the high levels of c-myb transcripts in
erythroleukemias may reflect the undifferentiated state of the leukemic cells.
In contrast, the elevated expression of c-myc and c-K-ras at both stages of the
Friend diseases is probably not related to the stage of differentiation but
rather to the uncontrolled proliferation of the cells. Finally among 18
protooncogenes surveyed, only the accumulation of c-myc and c-K-ras RNAs appears
to be associated with the Friend erythroleukemic process before the late
leukemic phase develops.

PMID: 3164254 [PubMed - indexed for MEDLINE]


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73: Clin Immunol Immunopathol. 1987 Dec;45(3):424-39. 

Protooncogene expression in peripheral blood mononuclear cells from patients
with systemic lupus erythematosus as an indicator of the disease activity.

Deguchi Y, Hara H, Negoro S, Kakunaga T, Kishimoto S.

Department of Oncogene Research, Osaka University, Japan.

In the present study, we examined the various protooncogene expressions in PBMC
(peripheral blood mononuclear cell) of systemic lupus erythematosus (SLE)
patients to determine if they could be an indicator for the disease activity. We
divided SLE patients into "very active," "active," and "remitting" states
according to the clinical symptoms in addition to the laboratory data peculiar
to SLE. In addition, we determined the amount of circulating immune complex (IC)
as one of the representative laboratory indicators for the disease activity. We
found a positive correlation with either c-myc or c-myb expression and the
amounts of IC and clinical disease activity. The degree of c-myc and c-myb
expression was significantly reduced along with or prior to the amelioration of
clinical symptoms and improvement as determined by laboratory data under
treatment with prednisolone and/or azathioprine administration. The degree of
c-myc and c-myb gene expression had no direct relation to the presence of
particular clinical sign(s) or autoantibody. The expression of the c-raf gene
was found in SLE and other systemic autoallergic patients although it showed no
correlation with the disease activity. No significant expression of c-src,
c-ras, c-fos, c-fgr, c-fps, c-fes, c-fms, c-yes, c-rel, c-abl, c-mos, c-sis, and
c-erb B genes was found in the patients. c-myc and c-myb expression as having
pathogenic and clinical significance is discussed.

PMID: 3677489 [PubMed - indexed for MEDLINE]


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74: Biochem Biophys Res Commun. 1987 Feb 13;142(3):932-8. 

The expression of oncogenes in human developing liver and hepatomas.

Zhang XK, Huang DP, Chiu DK, Chiu JF.

Oncogene expression was examined in the human fetal liver and human hepatomas.
Erb (B), erb (A+B), Ha-ras, myc, fos and fms oncogene expression elevated in
certain stages of fetal liver development and in hepatoma as compared to the
normal adult human liver. In contrast, rel, src, mos, sis, myb, Ki-ras and bas
oncogenes showed no apparent change of their mRNA levels during fetal liver
development and in hepatoma. Further study of erb B oncogene expression in human
cirrhotic liver and hepatoma demonstrated a strong correlation between erb B
expression and alteration of its gene structure.

PMID: 3030308 [PubMed - indexed for MEDLINE]


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75: Nucleic Acids Res. 1987 Jan 12;15(1):87-103. 

Replication of proto-oncogenes early during the S phase in mammalian cell lines.

Iqbal MA, Chinsky J, Didamo V, Schildkraut CL.

Members of several classes of proto-oncogenes replicate during the first third
of S-phase in two human (K562 erythroleukemia and HeLa), one Chinese hamster
(CHO) and eight mouse cell lines. These cell lines exhibit a variety of
specialized functions characteristic of pre-B and B cells, T cells and erythroid
cells. The proto-oncogenes studied include fos, myc, myb, abl, fes, fms, mos,
raf, rel, sis, Ha-ras, Ki-ras, and N-ras. In K562 cells, amplified and
rearranged c-abl genes show a pattern of temporal replication during S that is
similar to the pattern observed for the 5' breakpoint cluster region (bcr) and
the amplified C lambda light chain immunoglobulin genes. The c-Ki-ras related
sequences in CHO cells provide one example of late replicating proto-oncogene
sequences that are present in multiple copies. The cellular gene N-myc
replicates late during S in some of these cell lines. In three pre-B cell lines
in which N-myc specific transcripts have been detected, N-myc replicates earlier
in the S phase than in the other cell lines studied here.

PMID: 3469620 [PubMed - indexed for MEDLINE]


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76: Cancer Res. 1986 Oct;46(10):5302-11. 

Enhanced expression of c-myc and decreased expression of c-fos protooncogenes in
chemically and radiation-transformed C3H/10T1/2 Cl 8 mouse embryo cell lines.

Shuin T, Billings PC, Lillehaug JR, Patierno SR, Roy-Burman P, Landolph JR.

c-abl, c-fos, c-Ha-ras, c-myc, and c-mos were expressed whereas c-sis, c-fms,
c-rel, c-src, and c-myb expression was not detectable in C3H/10T1/2 Cl 8
(10T1/2) cells and in eight chemically and radiation-transformed 10T1/2 cell
lines. The expression of c-abl, c-fos, c-Ha-ras, and c-myc was growth-related in
nontransformed 10T1/2 cells. c-abl and c-fos expression increased at confluence
by 5- and 9-fold, respectively, compared to that in log phase cells. c-Ha-ras
and c-myc transcripts were most abundant in log phase cells and decreased by 70
and 50%, respectively, in confluent cells. There were no significant
growth-related changes in the expression of c-Ha-ras, c-myc, or c-abl in
methylcholanthrene-transformed Cl 15 cells. The c-fos transcript was not
detected in Cl 15 cell cultures. c-abl, c-fos, c-ras, and c-myc were expressed
in whole C3H mouse embryo tissue, mouse liver, and 10T1/2 cells. Sizes of these
protooncogene transcripts in 10T1/2 cells were the same as those in whole embryo
tissue, except that 10T1/2 cells did not express the 8.2-kilobase abl
transcript. At subconfluence, equivalent low levels of c-mos expression were
observed in nontransformed and in the eight transformed 10T1/2 cell lines. The
level of c-abl expression was similar in the nontransformed and in the eight
transformed cell lines, but there was a new 8.2-kilobase transcript in the
transformed MCA Cl 15 cell line. c-fos was expressed in 10T1/2 cells but was not
detectable or greatly reduced in eight transformed cell lines. c-Ha-ras was
expressed to a similar extent in eight transformed cell lines and in
nontransformed 10T1/2 cells. In the UVC-4 transformed cell line, extra
3.3-kilobase Ha-ras and 7.5-kilobase Ki-ras transcripts were observed. c-myc was
expressed at 4- to 7-fold higher levels in six transformed cell lines compared
to 10T1/2 cells. There were no major rearrangements in or amplification of the
c-myc gene in three transformed cells overexpressing this gene 5-fold. These
studies show that enhanced expression of c-myc and decreased expression of c-fos
correlate with the chemically and radiation transformed states of 10T1/2 cells.
Changes in c-fos and c-myc oncogene expression may be casually linked to late
stages of neoplastic transformation in these chemically and radiation
transformed 10T1/2 cell lines.

PMID: 2875790 [PubMed - indexed for MEDLINE]


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77: J Virol. 1986 Jan;57(1):371-5. 

Oncogene expression in reticuloendotheliosis virus-transformed lymphoid cell
lines and avian tissues.

Herzog NK, Bargmann WJ, Bose HR Jr.

The genome of reticuloendotheliosis virus (REV-T) contains a unique oncogene,
designated v-rel, which is inserted into the env region. Employing a cloned rel
DNA probe, a single 2.9- to 3.0-kilobase v-rel mRNA was identified in poly(A)+
RNA from REV-T-transformed lymphoid cell lines. A 4.0-kilobase rel-specific
transcript corresponding to the cellular homolog of the v-rel oncogene was
identified in MSB-1 cells, a herpesvirus-transformed lymphoid cell line. Cytodot
hybridization was used to quantitate the levels of rel, c-rel, c-myc, c-myb,
c-abl, c-fms, c-Ha-ras, c-Ki-ras, c-src, c-yes, c-mos, and c-sis mRNA in
REV-T-transformed cells. The levels of rel transcription in REV-T-transformed
cells were elevated only two to eightfold over levels found in the transformed
immature avian lymphoid cell line MSB-1. The relatively modest levels of rel
transcription in REV-T-transformed cells and the significant differences between
the lengths of the v-rel and c-rel mRNA suggest that REV-T transformation is the
result of the production of an altered rel protein. The c-rel proto-oncogene is
expressed in all avian hematopoietic tissues but is not expressed at significant
levels in brain and muscle. The transcription of other proto-oncogenes is not
enhanced in REV-T-transformed lymphoid cell lines.

PMID: 2867231 [PubMed - indexed for MEDLINE]


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78: Virology. 1985 Aug;145(1):154-64. 

Avian retrovirus S13: properties of the genome and of the
transformation-specific protein.

Benedict SH, Maki Y, Vogt PK.

The avian retrovirus S13 codes for an env-linked transformation-specific
glycoprotein with a molecular weight of 155,000 (gp155). Treatment of gp155 with
endoglycosidase H or growth of S13-infected cells in the presence of tunicamycin
reduces the molecular weight of gp155 to about 140K, but these gp155-related
molecules may still contain sugar residues. The gp155 protein is not
incorporated into virions; it is phosphorylated, but in immunoprecipitates does
not show protein kinase activity. The genome of S13 is an 8.5-kilobase (kb) RNA;
the helper virus genome is 7.5 kb in size. The putative onc sequences of S13 do
not hybridize to DNA probes representing src, erb A, erb B, myc, myb, fps, fms,
H-ras, B-lym, abl, rel, and ets.

PMID: 2990097 [PubMed - indexed for MEDLINE]


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79: Virology. 1985 Jul 15;144(1):115-26. 

Oncogene expression in murine splenic T cells and in murine T-cell neoplasms.

Mally MI, Vogt M, Swift SE, Haas M.

The differential expression of a series of proto-oncogenes has been examined in
a group of cultured murine T-cell lymphomas that were induced following virus
inoculation into, or X irradiation of, C57BL/6 mice. Two classes of T lymphoma
cell lines were studied: growth factor-dependent (autocrine) cells, and growth
factor-independent T lymphoma cells. Cell lines that were established from
X-irradiation-induced T lymphomas were growth factor dependent, whereas T
lymphoma lines grown from virus-induced tumors were generally growth factor
independent. Of 18 cellular proto-oncogenes studied, five (c-myc, c-myb, c-abl,
c-rasHa, c-rasKi) were consistently expressed in all cell lines tested. Thirteen
other proto-oncogenes (c-mos, c-sis, c-rel, c-yes, c-fes3, c-fes4, c-fos, c-fms,
c-src, c-erbA, c-erbB, int-1, Pim-1) were not expressed in any of the T lymphoma
cells tested. Concanavalin A-stimulated spleen cells, representative of
replicating T cells, expressed c-myc, c-abl, and Pim-1, suggesting that the
products of these proto-oncogenes are involved in T-cell proliferation. The
results indicate no qualitative differences (albeit some quantitative
differences) in proto-oncogene expression between the growth factor-dependent
and growth factor-independent cells. This suggests that expression of the five
proto-oncogenes is in itself not sufficient to induce the progression of the
growth factor-dependent cells to their fully growth factor-independent
counterparts. Changes in the regulation of one or more of the five active
proto-oncogenes, i.e., from an inducible to a constitutive state, and/or
additional changes in the expression of other cellular genes may be required to
induce the transformation of neoplastic T cells from growth factor dependence to
growth factor independence.

PMID: 2414915 [PubMed - indexed for MEDLINE]


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80: Cancer Res. 1983 Aug;43(8):3912-8. 

Transcription of hematopoietic-associated oncogenes in childhood leukemia.

Rosson D, Tereba A.

We have examined the transcriptional expression of the cellular homologues of
several retrovirus-associated oncogenes, myc, rel, rasH, myb, src, and erb, in
uncultured childhood leukemia and normal hematopoietic cells, as a first step in
determining their normal function and possible association with human neoplasia.
Cellular myc-specific RNA was detected in all 30 samples of hematopoietic tissue
examined, including 18 leukemias of both the lymphoid and myeloid series, three
lymphomas, five normal leukocytes, and four cell lines. Although the level of
expression varied over a 25-fold range, no general pattern based on cell type or
disease state was evident. In addition, in all cell types examined, a
single-molecular-weight myc-specific RNA species was observed. Transcriptional
expression of the rel and rasH genes showed a similar lack of specificity, with
the rasH gene being expressed at a low uniform level in all cell types examined.
myb expression was marginally detectable in most samples, although the myeloid
leukemia cells possessed approximately 4-fold higher levels. The expression of
src was relatively low in most samples, with markedly elevated levels in a few
diverse leukemia samples. erb expression was undetectable in all but two acute
myelogenous leukemia samples. Analysis of one patient who had high levels of
myc, erb, and src expression before therapy revealed a dramatic reduction in erb
and src expression but not myc expression while the patient was in remission.
These results indicate that primary human leukemia cells, as well as normal
leukocytes, do express the cell homologues to several retrovirus-associated
oncogenes, that some leukemia cells express high levels of several oncogenes,
and that some of these genes are differentially expressed in specific
subpopulations of cells.

PMID: 6861153 [PubMed - indexed for MEDLINE]


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