1: Cell Biol Int. 2005 Jun;29(6):429-40. Epub 2005 Mar 25.
Apoptosis effects of Xrel3 c-Rel/Nuclear Factor-kappa B homolog in human
cervical cancer cells.
Shehata M, Shehata M, Shehata F, Pater A.
Division of Basic Sciences, Faculty of Medicine, Memorial University of
Newfoundland, St. John's, NF A1B 3V6, Canada. mshehata@ottawaheart.ca
Cervical cancer is considered a common yet preventable cause of death in women.
In this report, we studied the role of the NF-kappaB gene family in HeLa human
cervical cancer cells, using the Xrel3 c-Rel homologue of Xenopus laevis. The
expression of Xrel3/c-Rel slowed cell growth 6-fold, consistent with an
upregulated expression of the cell cycle inhibitor p21. The activated PARP
apoptosis effector was significantly increased (P<0.01). Based on cell viability
assays Xrel3 provided an anti-apoptotic effect in 1 microM cisplatin, and this
was associated with significantly lower levels of the apoptotic proteins Bax and
MDM-2 (P<0.05). Furthermore, there was a 3-fold drop in the level of the tumor
suppressor protein p53. In 5 microM cisplatin, expression of HeLa Xrel3 enhanced
apoptosis by significantly increasing the expression of the apoptotic proteins
Bax and MDM-2 (P<0.05). However, the tumor suppressor protein p53 showed a
significant decrease (P<0.05) relative to the control. Thus, c-Rel/NF-kappaB may
potentially be of clinical significance, especially in tumors exhibiting
resistance to high-level chemotherapy.
PMID: 16054560 [PubMed - in process]
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2: Oncogene. 2005 Sep 29;24(43):6574-83.
Immortalized fibroblasts from NF-kappaB RelA knockout mice show phenotypic
heterogeneity and maintain increased sensitivity to tumor necrosis factor alpha
after transformation by v-Ras.
Gapuzan ME, Schmah O, Pollock AD, Hoffmann A, Gilmore TD.
Department of Biology, Boston University, 5 Cummington Street, Boston, MA 02215,
USA.
Activation of the NF-kappaB pathway can either promote or block apoptosis and
oncogenesis in different cell types and circumstances. In this report, we show
that independently derived immortalized mouse embryonic fibroblast cell lines
prepared from RelA knockout mice have different phenotypes, based on their
sensitivity to tumor necrosis factor alpha (TNFalpha)-induced apoptosis,
morphology, ability to form colonies in soft agar, and the presence of distinct
kappaB site-binding complexes. In addition, these RelA-deficient cell lines
appear to have distinct alterations in the p53 pathway, which correlate with the
normal vs transformed status of individual cell lines. We have also infected
mouse embryonic fibroblasts lacking RelA, c-Rel or p50 with a retrovirus for the
expression of v-Ha-Ras to determine whether individual NF-kappaB family members
are required for Ras-mediated transformation. All three NF-kappaB-deficient cell
types could be transformed by v-Ha-Ras. However, v-Ras-infected RelA-deficient
cells formed colonies in soft agar at an approximately fourfold reduced
efficiency compared to v-Ras-transformed control mouse 3T3 and p50-deficient
cells. Ras transformation did not alter the sensitivity of RelA-deficient cells
to TNFalpha-induced apoptosis, and Ras transformation did not affect the general
resistance of 3T3, c-Rel-deficient, and p50-deficient cells to TNFalpha-induced
apoptosis. However, TNFalpha specifically and dose-dependently decreased the
ability of v-Ras-transformed RelA-deficient cells to form colonies in soft agar.
These results suggest that RelA is a potential protein target for human tumors
driven by oncogenic Ras mutations, but caution that inhibition of RelA may
promote tumorigenesis in some circumstances.
PMID: 16027734 [PubMed - indexed for MEDLINE]
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3: Histopathology. 2005 Jul;47(1):101-10.
Large B-cell lymphoma with Hodgkin's features.
Garcia JF, Mollejo M, Fraga M, Forteza J, Muniesa JA, Perez-Guillermo M,
Perez-Seoane C, Rivera T, Ortega P, Piris MA.
Lymphoma Group, Molecular Pathology Programme, Centro Nacional de
Investigaciones Oncologica (CNIO), Madrid, Spain. jfgarcia@cnio.es
AIMS: To describe the features of a series of nine cases of diffuse large B-cell
lymphoma (DLBCL) showing morphological and immunophenotypic features that are
intermediate with Hodgkin's lymphoma (HL). METHODS AND RESULTS: Most cases (6/9)
presented as mediastinal tumours affecting young males, while the other three
cases arose in extramediastinal locations. Histopathologically, tumours showed
diffuse large cell areas in a polymorphous background, with pleomorphic cytology
and the common presence of Hodgkin's and Reed-Sternberg cells.
Immunophenotypically, tumours shared features of DLBCL and classical HL, with
expression of CD30, CD15 (6/9), and a full B-cell profile including CD45RB,
CD20, CD79a and OCT2. Epstein-Barr virus-latent membrane protein expression was
found in 2/9 cases. The majority of tumours had immunohistochemical features
consistent with activation of the NF-(kappa)B pathway, including nuclear
location of the c-REL/p65 subunit, overexpression of phosphorylated
I(kappa)B(alpha), and overexpression of NF-(kappa)B targets. Finally, 2/9 cases
showed 3q27 (BCL6) rearrangement, and 1/9 had p53 gene mutations, both of which
are rarely detected in classical HL. CONCLUSIONS: These findings suggest that
DLBCLs with HL features constitute a distinctive subgroup of aggressive
lymphomas whose neoplastic growth and peculiar characteristics could be
facilitated by a particular microenvironment found in the mediastinum.
PMID: 15982329 [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: Genes Chromosomes Cancer. 2003 Nov;38(3):240-8.
Pattern of secondary genomic changes in pancreatic tumors of Tgf alpha/Trp53+/-
transgenic mice.
Schreiner B, Baur DM, Fingerle AA, Zechner U, Greten FR, Adler G, Sipos B,
Kloppel G, Hameister H, Schmid RM.
Department of Human Genetics, University of Ulm, Ulm, Germany.
Trp53(+/-) mice overexpressing Tgfalpha in a pancreas-specific manner represent
a well-established animal model for pancreatic cancer. In this study we analyzed
38 pancreatic adenocarcinomas of these mice for secondary genomic changes by
comparative genomic hybridization (CGH), loss of heterozygosity (LOH) analysis,
real-time PCR, and methylation-specific analysis. CGH screening of the tumors
revealed a recurrent pattern of genomic changes. In more than 50% of the tumors,
chromosome 11 was affected. The gain of the proximal part spans about 16 cM,
including the genes for Egfr, Rel, and Stk10. The distal part of chromosome 11,
which contains the Trp53 locus, was deleted. LOH analysis proved that almost all
tumors segregate the wild-type Trp53 allele. The Cdkn2a locus on chromosome 4
was inactivated by hypermethylation in 55% of all tumors. In addition, two other
changes were detected in a mutually exclusive manner: overrepresentation of part
of chromosome 15, or more rarely, loss of the distal part of chromosome 14.
Together these data suggest the induction of a uniform pattern of secondary
genomic changes in this transgenic tumor model for pancreatic cancer. Copyright
2003 Wiley-Liss, Inc.
PMID: 14506698 [PubMed - indexed for MEDLINE]
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6: 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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7: 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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8: 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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9: Int Immunopharmacol. 2002 Jul;2(8):1065-77.
Lipopeptide adjuvants: monitoring and comparison of P3CSK4- and LPS-induced gene
transcription.
Muller MR, Wiesmuller KH, Jung G, Loop T, Humar M, Pfannes SD, Bessler WG,
Mittenbuhler K.
Institut fur Molekulare Medizin und Zellforschung der Universitat Freiburg, AK
Tumorimmunologie/Vakzine, Germany.
Bacteria-derived synthetic lipoproteins constitute potent macrophage activators
in vivo and are effective stimuli, enhancing the immune response especially with
respect to low or non-immunogenic compounds.
N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,S)-propyl]-(R)-cysteinyl-seryl-(lysyl)3
-lysine (P3CSK4), exhibiting one of the most effective lipopeptide derivatives,
represents a highly efficient immunoadjuvant in parenteral, oral, nasal and
genetic immunization either in combination with or after covalent linkage to
antigen. In order to further elucidate its molecular mode of action with respect
to the transcriptional level, we focused our investigations on the
P3CSK4-induced modulation of gene transcription. We could show that P3CSK4
activates/represses an array of at least 140 genes partly involved in signal
transduction and regulation of the immune response. P3CSK4 activates the
expression of tumor suppressor protein p53 (p53), c-rel, inhibitor of nuclear
factor kappa B (NFkappaB) alpha (IkappaB alpha), type 2 (inducible) nitric oxide
(NO) synthase (iNOS), CD40-LR, intercellular adhesion molecule-1 (ICAM-1) and
interleukin 1/6/15 (IL-1/6/15). We detected no activation of heat shock protein
(HSP) 27, 60, 84 and 86, osmotic stress protein 94 (Osp 94), IL-12,
extracellular signal-regulated protein kinase 1 (ERK1), p38 mitogen activated
protein (MAP)-kinase (p38), c-Jun NH2-terminal kinase (JNK), signal transducer
and activator of transcription 1 (STAT1), CD14 and caspase genes. Furthermore,
we monitored inhibition of STAT6, Janus kinase 3 (Jak3) and cyclin D1/D3 gene
transcription after stimulating bone marrow-derived macrophages (BMDM) with
lipopeptide. In addition, we monitored significant differences after lipopeptide
and lipopolysaccharide (LPS) stimulation of bone marrow-derived murine
macrophages. Our findings are of importance for further optimizing both
conventional and genetic immunization, and for the development of novel
synthetic vaccines.
PMID: 12349944 [PubMed - indexed for MEDLINE]
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10: Cell Death Differ. 2002 Mar;9(3):252-63.
Role of glutathione depletion and reactive oxygen species generation in
apoptotic signaling in a human B lymphoma cell line.
Armstrong JS, Steinauer KK, Hornung B, Irish JM, Lecane P, Birrell GW, Peehl DM,
Knox SJ.
Department of Radiation Oncology, Stanford University, Stanford, California, CA
94305-5105, USA.
The primary objective of this study was to determine the sequence of biochemical
signaling events that occur after modulation of the cellular redox state in the
B cell lymphoma line, PW, with emphasis on the role of mitochondrial signaling.
L-Buthionine sulphoximine (BSO), which inhibits gamma glutamyl cysteine
synthetase (gammaGCS), was used to modulate the cellular redox status. The
sequence and role of mitochondrial events and downstream apoptotic signals and
mediators was studied. After BSO treatment, there was an early decline in
cellular glutathione (GSH), followed by an increase in reactive oxygen species
(ROS) production, which induced a variety of apoptotic signals (detectable at
different time points) in the absence of any external apoptotic stimuli. The
sequence of biochemical events accompanying apoptosis included a 95% decrease in
total GSH and a partial (25%) preservation of mitochondrial GSH, without a
significant increase in ROS production at 24h. Early activation and nuclear
translocation of the nuclear factor kappa B subunit Rel A was observed at
approximately 3h after BSO treatment. Cytochrome c release into the cytosol was
also seen after 24h of BSO treatment. p53 protein expression was unchanged after
redox modulation for up to 72 h, and p21waf1 independent loss of cellular
proliferation was observed. Surprisingly, a truncated form of p53 was expressed
in a time-dependent manner, beginning at 24h after BSO incubation. Irreversible
commitment to apoptosis occurred between 48 and 72 h after BSO treatment when
mitochondrial GSH was depleted, and there was an increase in ROS production.
Procaspase 3 protein levels showed a time-dependent reduction following
incubation with BSO, notably after 48 h, that corresponded with increasing ROS
levels. At 96 h, caspase 3 cleavage products were detectable. The pan-caspase
inhibitor zVADfmk, partially blocked the induction of apoptosis at 48 h, and was
ineffective after 72 h. PW cells could be rescued from apoptosis by removing
them from BSO after up to 48, but not 72 h incubation with BSO. Mitochondrial
transmembrane potential (DeltaPsi(m)) remained intact in most of the cells
during the 72 h observation period, indicating that DeltaPsi(m) dissipation is
not an early signal for the induction of redox dependent apoptosis in PW cells.
These data suggest that a decrease in GSH alone can act as a potent early
activator of apoptotic signaling. Increased ROS production following
mitochondrial GSH depletion, represents a crucial event, which irreversibly
commits PW cells to apoptosis.
PMID: 11859408 [PubMed - indexed for MEDLINE]
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11: Nat Cell Biol. 2001 Apr;3(4):409-16.
Regulation of death receptor expression and TRAIL/Apo2L-induced apoptosis by
NF-kappaB.
Ravi R, Bedi GC, Engstrom LW, Zeng Q, Mookerjee B, Gelinas C, Fuchs EJ, Bedi A.
Johns Hopkins Oncology Center, The Johns Hopkins University School of Medicine,
Bunting-Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore,
Maryland 21231, USA.
TRAIL (tumour-necrosis factor-related apoptosis ligand or Apo2L) triggers
apoptosis through engagement of the death receptors TRAIL-R1 (also known as DR4)
and TRAIL-R2 (DR5). Here we show that the c-Rel subunit of the transcription
factor NF-kappaB induces expression of TRAIL-R1 and TRAIL-R2; conversely, a
transdominant mutant of the inhibitory protein IkappaBalpha or a
transactivation-deficient mutant of c-Rel reduces expression of either death
receptor. Whereas NF-kappaB promotes death receptor expression,
cytokine-mediated activation of the RelA subunit of NF-kappaB also increases
expression of the apoptosis inhibitor, Bcl-xL, and protects cells from TRAIL.
Inhibition of NF-kappaB by blocking activation of the IkappaB kinase complex
reduces Bcl-x L expression and sensitizes tumour cells to TRAIL-induced
apoptosis. The ability to induce death receptors or Bcl-xL may explain the dual
roles of NF-kappaB as a mediator or inhibitor of cell death during immune and
stress responses.
PMID: 11283615 [PubMed - indexed for MEDLINE]
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12: 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]
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13: 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]
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14: 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]
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15: J Virol. 1998 Nov;72(11):8852-60.
Human T-cell lymphotropic/leukemia virus type 1 Tax abrogates p53-induced cell
cycle arrest and apoptosis through its CREB/ATF functional domain.
Mulloy JC, Kislyakova T, Cereseto A, Casareto L, LoMonico A, Fullen J, Lorenzi
MV, Cara A, Nicot C, Giam C, Franchini G.
Basic Research Laboratory, Division of Basic Sciences, National Cancer
Institute, Bethesda, Maryland 20892, USA. jmulloy@helix.nih.gov
Human T-cell lymphotropic/leukemia virus type 1 (HTLV-1) transforms human T
cells in vitro, and Tax, a potent transactivator of viral and cellular genes,
plays a key role in cell immortalization. Tax activity is mediated by
interaction with cellular transcription factors including members of the
CREB/ATF family, the NF-kappaB/c-Rel family, serum response factor, and the
coactivators CREB binding protein-p300. Although p53 is usually not mutated in
HTLV-1-infected T cells, its half-life is increased and its function is
impaired. Here we report that transient coexpression of p53 and Tax results in
the suppression of p53 transcriptional activity. Expression of Tax abrogates
p53-induced G1 arrest in the Calu-6 cell line and prevents the apoptosis induced
by overexpressing p53 in the HeLa/Tat cell line. The Tax mutants M22 and G148V,
which selectively activate the CREB/ATF pathway, exert these same biological
effects on p53 function. In contrast, the NF-kappaB-active Tax mutant M47 has no
effect on p53 activity in any of these systems. Consistent with the negative
effect of Tax on p53, no activity on a p53-responsive promoter was observed upon
transfection of HTLV-1-infected T-cell lines. The p53 protein is expressed at
high levels in the nucleus, and nuclear extracts of HTLV-1-infected T cells bind
constitutively to a DNA oligonucleotide containing the p53 response element,
indicating that Tax does not interfere with p53 binding to DNA. Tax is able to
suppress the transactivation function of p53 in three different cell lines, and
this suppression required Tax-mediated activation of the CREB/ATF, but not the
NF-kappaB/c-Rel, pathway. Tax and the active Tax mutants were able to abrogate
the G1 arrest and apoptosis induced by p53, and this effect does not correlate
with an altered localization of nuclear p53 or with the disruption of p53-DNA
complexes. The suppression of p53 activity by Tax could be important in T-cell
immortalization induced by HTLV-1.
PMID: 9765430 [PubMed - indexed for MEDLINE]
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16: 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]
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17: Mutat Res. 1997 Nov 19;381(1):67-75.
Modulation of NF-kappa B, and Bcl-2 in apoptosis induced by cisplatin in HeLa
cells.
Maldonado V, Melendez-Zajgla J, Ortega A.
Laboratorio de Biologia Molecular, Instituto Nacional de Cancerologia, Mexico
City, Mexico.
Cisplatin exposure induces apoptosis in HeLa cells. Since the interaction of
this drug with DNA produces reactive oxygen species, we performed an analysis of
the oxidative stress-responsive factors AP-1 and NF-kappa B. Although AP-1
levels were not modified during cisplatin exposure, electrophoretic mobility
shift assays demonstrated an increase in NF-kappa B DNA binding activity that
correlated with a decrease of the inhibitory protein I kappa B alpha and a
specific relocalization of c-Rel, as assessed by immunoblotting and
immunofluorescence. No changes in the levels or localization of p65 were found.
Interestingly, I kappa B alpha relocalized to the nucleus, probably in order to
regulate the binding of specific complexes. This process was accompanied by a
decrease of the antiapoptotic protein Bcl-2, and a relocalization of p53 protein
to the nucleus. Since HeLa cells lost most of their p53 protein due to a
specific E6-dependent degradation, cisplatin could be inhibiting this
degradation, since the p53 total levels were not increased during the exposure
to the drug.
PMID: 9403032 [PubMed - indexed for MEDLINE]
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18: Mol Cell Biol. 1997 Nov;17(11):6526-36.
c-Rel arrests the proliferation of HeLa cells and affects critical regulators of
the G1/S-phase transition.
Bash J, Zong WX, Gelinas C.
Center for Advanced Biotechnology and Medicine, and Graduate Program in
Microbiology and Molecular Genetics, Rutgers University, Piscataway, New Jersey
08854, USA.
A tetracycline-regulated system was used to characterize the effects of c-Rel on
cell proliferation. The expression of c-Rel in HeLa cells led to growth arrest
at the G1/S-phase transition, which correlated with its nuclear localization and
the induction of endogenous IkappaB alpha expression. These changes were
accompanied by a decrease in E2F DNA binding and the accumulation of the
hypophosphorylated form of Rb. In vitro kinase assays showed a reduction in Cdk2
kinase activity that correlated with elevated levels of p21WAF1 Cdk inhibitor
and p53 tumor suppressor protein. While the steady-state levels of WAF1
transcripts were increased, pulse-chase analysis revealed a sharp increase in
p53 protein stability. Importantly, the deletion of the C-terminal
transactivation domains of c-Rel abolished these effects. Together, these
studies demonstrate that c-Rel can affect cell cycle control and suggest the
involvement of the p21WAF1 and p53 cell cycle regulators.
PMID: 9343416 [PubMed - indexed for MEDLINE]
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19: 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]
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20: 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]
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22: Oncogene Res. 1988;2(2):149-65.
Localization of Evi-2 to chromosome 11: linkage to other proto-oncogene and
growth factor loci using interspecific backcross mice.
Buchberg AM, Bedigian HG, Taylor BA, Brownell E, Ihle JN, Nagata S, Jenkins NA,
Copeland NG.
Mammalian Genetics Laboratory, BRI-Basic Research Program, NCI-Frederick Cancer
Research Facility, Maryland 21701.
A common site of ecotropic murine leukemia virus integration designated Evi-2
(ecotropic viral integration site-2) has been identified in BXH-2 myeloid
tumors. As part of experiments to determine whether Evi-2 identified a new
proto-oncogene locus involved in myeloid disease, we determined its chromosomal
location. We mapped Evi-2 to mouse Chromosome 11 using standard recombinant
inbred strain and genetic backcross analysis. We then determined the location of
Evi-2 relative to other proto-oncogene and growth factor loci located on
Chromosome 11 by interspecific backcross analysis. The loci included in this
study were the proto-oncogene loci, Erbb, Erba, and Rel, as well as, Il-3
(interleukin-3), Csfgm (granulocyte-macrophage colony stimulating factor), and
Trp53-1 (transforming protein p53). All loci except Erbb had been previously
mapped to Chromosome 11 with the use of somatic cell hybrids and consequently
their positions on Chromosome 11 were not known. One proto-oncogene, Erbb-2
(analogous to the neu proto-oncogene), and one growth factor locus, Csfg
(granulocyte colony-stimulating factor), which had not been mapped in the mouse
were also localized on Chromosome 11 using the interspecific backcross mice.
Recombination between Evi-2 and all proto-oncogene and growth factor loci was
demonstrated, suggesting that Evi-2 may ultimately identify a new proto-oncogene
involved in myeloid disease. This study revealed a number of interesting
conserved linkage groups common to mouse and man.
PMID: 2851124 [PubMed - indexed for MEDLINE]
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