1: Leuk Res. 2004 Nov;28(11):1227-37. 

Analysis of the relationship between Scl transcription factor complex protein
expression patterns and the effects of LiCl on ATRA-induced differentiation in
blast cells from patients with acute myeloid leukemia.

Rice AM, Holtz KM, Karp J, Rollins S, Sartorelli AC.

Department of Pharmacology, Cancer Center, Yale University School of Medicine,
333 Cedar Street, New Haven, CT 06520, USA.

Exogenous expression of the transcription factor Scl (Tal1) in WEHI-3B D+
myelomonocytic leukemia cells interferes with their capacity to respond to
all-trans retinoic acid (ATRA) induced differentiation; combination of ATRA with
LiCl, however, circumvents the inhibition of differentiation produced by Scl. To
gain information on the possible involvement of this transcription factor in the
non-responsiveness of acute myelocytic leukemia (AML) patients to ATRA, we
compared the endogenous expression levels of Scl and its transcription complex
partners [i.e., Rbtn1 (LMO1), Rbtn2 (LMO2), Ldb1, and GATA family proteins] in
leukemic blast cells from patients with AML and acute promyelocytic leukemia
(APL), and determined the effects of lithium chloride alone or in combination
with ATRA on the capacity of blast cells to differentiate during short-term ex
vivo culture. Levels of Scl, Rbtn2, GATA1, and Ldb1 expression were comparable
in AML and APL blasts, while the levels of expression of Rbtn1, GATA2, and GATA3
were absent or markedly lower in APL cells. Differentiation markers (cell
surface myeloid antigens CD11b, CD15, CD14, and CD33) were also analyzed in
blast cells. ATRA produced changes in at least one surface antigen
differentiation marker in 89% of patient blasts, while LiCl caused such changes
in 72% of the leukemic cells of patients. The combination of LiCl and ATRA
induced the differentiation of leukemic blasts from 94% of patients. Although
the expression of the transcription factors did not act as individual predictors
of responsiveness or non-responsiveness to the inducers of differentiation, ATRA
or ATRA plus LiCl, the addition of LiCl to ATRA increased the differentiation
response over that of ATRA alone in a number of leukemic samples. These findings
suggest that the combination of LiCl and ATRA may produce some clinical benefit
in the treatment of the myeloid leukemias.

PMID: 15380350 [PubMed - indexed for MEDLINE]


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2: Hum Cell. 2004 Jun;17(2):85-92. 

Transcription factor expression in cell lines derived from natural killer-cell
and natural killer-like T-cell leukemia-lymphoma.

Matsuo Y, Drexler HG, Harashima A, Okochi A, Shimizu N, Orita K.

Fujisaki Cell Center, Hayashibara Biochemical Labs, Okayama 702-8006, Japan.
yomatsuo@hayashibara.co.jp

Although a number of transcription factors (TFs) have been identified that play
a pivotal role in the development of hematopoietic lineages, only little is
known about factors that may influence development and lineage commitment of
natural killer (NK) or NK-like T (NKT)-cells. Obviously to fully appreciate the
NK- and NKT-cell differentiation process, it is important to identify and
characterize the TFs effecting the NK- and NKT-cell lineage. Furthermore, these
TFs may play a role in NK- or NKT-cell leukemias, in which the normal
differentiation program is presumably disturbed. The present study analyzed the
expression of the following 13 TFs: AML1, CEBPA, E2A, ETS1, GATA1, GATA2, GATA3,
IKAROS, IRF1, PAX5, PU1, TBET and TCF1 in 7 malignant NK-cell lines together
with 5 malignant NKT-cell lines, 5 T-cell acute lymphoblastic leukemia (ALL)
cell lines including 3 gamma/delta T-cell receptor (TCR) type and 2 alpha/beta
TCR type, and 3 B-cell precursor (BCP) leukemia cell lines. AML1, E2A, ETS1,
IKAROS and IRF1 were found to be positive for all cell lines tested whereas
GATA1 turned out to be universally negative. CEBPA, PAX5 and PU1 were negative
for all cell lines tested except in the three positive BCP-cell lines. GATA2 was
positive for 3/5 T-cell lines but negative for the other cell lines. GATA3 was
positive for 7/7 NK-, 4/5 NKT-, 5/5 T- and 2/3 BCP-cell lines. TBET was positive
for all NK- and NKT-cell lines and negative for all T- and BCP-cell lines except
one BCP-cell line. In contrast to the expression of TBET, TCF1 was negative for
all NK- and NKT-cell lines, being positive for 4/5 T- and 1/3 BCP-cell lines.
Expression analysis of TFs revealed that NK- and NKT-cell lines showed identical
profiles, clearly distinct from those of the other T-ALL or BCP-ALL
leukemia-derived cell lines..

PMID: 15369140 [PubMed - indexed for MEDLINE]


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3: EMBO J. 2003 Aug 1;22(15):3887-97. 

Myeloid lineage switch of Pax5 mutant but not wild-type B cell progenitors by
C/EBPalpha and GATA factors.

Heavey B, Charalambous C, Cobaleda C, Busslinger M.

Research Institute of Molecular Pathology, Vienna Biocenter,Dr. Bohr-Gasse 7,
A-1030 Vienna, Austria.

The developmental potential of hematopoietic progenitors is restricted early on
to either the erythromyeloid or lymphoid lineages. The broad developmental
potential of Pax5(-/-) pro-B cells is in apparent conflict with such a strict
separation, although these progenitors realize the myeloid and erythroid
potential with lower efficiency compared to the lymphoid cell fates. Here we
demonstrate that ectopic expression of the transcription factors C/EBPalpha,
GATA1, GATA2 and GATA3 strongly promoted in vitro macrophage differentiation and
myeloid colony formation of Pax5(-/-) pro-B cells. GATA2 and GATA3 expression
also resulted in efficient engraftment and myeloid development of Pax5(-/-)
pro-B cells in vivo. The myeloid transdifferentiation of Pax5(-/-) pro-B cells
was accompanied by the rapid activation of myeloid genes and concomitant
repression of B-lymphoid genes by C/EBPalpha and GATA factors. These data
identify the Pax5(-/-) pro-B cells as lymphoid progenitors with a latent myeloid
potential that can be efficiently activated by myeloid transcription factors.
The same regulators were unable to induce a myeloid lineage switch in Pax5(+/+)
pro-B cells, indicating that Pax5 dominates over myeloid transcription factors
in B-lymphocytes.

PMID: 12881423 [PubMed - indexed for MEDLINE]


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4: Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2002 Apr;10(2):100-3. 

Sequence analysis of 5'-flanking region of human pax-5 gene exon 1B.

Liu ML, Rahman M, Hirabayashi Y, Sasaki T.

Department of Nephrology and Rheumatology, The Third Affiliated Hospital,
Jiangxi Medical College, Nanchang 330008, China.

Pax-5 gene is important transcription factor in B-lymphopoiesis and B-cell
development. To understand the regulatory mechanism of pax-5 expression, the
immediate 5'-flanking region (6 671 bp) of human pax-gene exon 1B was isolated
and characterized. Analysis of the total sequence showed that the proximal
promoter includes 3 CAT boxes, 1 SP1 and 1 E box. However, there was no
consensus sequence for a TATA box in the 5'-flanking region. Putative regulatory
sites of further upstream in the sequence revealed 6 LMO(2)COM, 5 NFAT, 2
LPOLYA-B, 3 GATA1, 2 AP4, 10 MZF1, 1 ETS1-B, 1 GATA3, 1 NKX25, 2 RORA1, 1 LYF1,
2 Ikaros2, 2 TCF11, 1 GATA-C and 1 FREAC7. Therefore, the 5'-flanking region of
human pax-5 exon 1B could be involved in regulating the expression of human
pax-5 and B-cell differentiation and development.

PMID: 12513807 [PubMed - indexed for MEDLINE]


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5: Transgenic Res. 1998 Jul;7(4):229-38. 

Loss of LKLF function results in embryonic lethality in mice.

Wani MA, Means RT Jr, Lingrel JB.

Department of Molecular Genetics, Biochemistry and Microbiology, College of
Medicine, University of Cincinnati, Ohio 45267-0524, USA.

Lung Kruppel-like factor (LKLF) is a member of the Kruppel-like family of zinc
finger transcription factors and is closely related to erythroid kruppel-like
factor (EKLF), which is necessary for beta-globin gene expression. While EKLF is
expressed exclusively in erythroid cells, LKLF is expressed temporally during
early embryonic development and predominantly in the adult mouse lung. To
understand the role this novel transcription factor plays in development as well
as tissue differentiation and function, animals lacking LKLF were produced using
gene targeting technology. Mice lacking LKLF die in utero between day 11.5 and
13.5 of embryonic life and exhibit retarded growth, craniofacial abnormalities,
abdominal bleeding and signs of anaemia. Although the yolk sac erythropoiesis is
normal in mutant embryos, in vitro fetal liver cultures of these embryos fail to
give rise to erythroid cells. Expression of other erythroid specific genes such
as EKLF, GATA1 and GATA3 is unaltered in these animals. These findings
demonstrate the LKLF function is indispensable during normal embryonic
development, and although both LKLF and EKLF recognize common DNA motifs, they
do not substitute for each other.

PMID: 9859212 [PubMed - indexed for MEDLINE]


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6: Biochem J. 1996 Jan 1;313 ( Pt 1):245-51. 

PEST motifs are not required for rapid calpain-mediated proteolysis of c-fos
protein.

Carillo S, Pariat M, Steff A, Jariel-Encontre I, Poulat F, Berta P, Piechaczyk
M.

Institut de Genetique Moleculaire de Montpellier/UMR 9942, France.

Cytoplasmic degradation of c-fos protein is extremely rapid. Under certain
conditions, it is a multi-step process initiated by calcium-dependent and
ATP-independent proteases called calpains. PEST motifs are peptide regions rich
in proline, glutamic acid/aspartic acid and serine/threonine residues, commonly
assumed to constitute built-in signals for rapid recognition by intracellular
proteases and particularly by calpains. Using a cell-free degradation assay and
site-directed mutagenesis, we report here that the three PEST motifs of c-fos
are not required for rapid cleavage by calpains. Testing the susceptibility of
PEST motif-bearing and non-bearing transcription factors including GATA1, GATA3,
Myo D, c-erbA, Tal-1 and Sry, demonstrates that PEST sequences are neither
necessary nor sufficient for specifying degradation of other proteins by
calpains. This conclusion is strengthened by the observation that certain
proteins, reportedly known to be cleavable by calpains, are devoid of PEST
motifs.

PMID: 8546691 [PubMed - indexed for MEDLINE]


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7: Genomics. 1994 May 1;21(1):1-6. 

Structure and expression of the human GATA3 gene.

Labastie MC, Bories D, Chabret C, Gregoire JM, Chretien S, Romeo PH.

INSERM U.91, Hopital Henri Mondor, Creteil, France.

GATA3, a member of the GATA family that is abundantly expressed in the
T-lymphocyte lineage, is thought to participate in T-cell receptor gene
activation through binding to enhancers. To understand GATA3 gene regulation, we
cloned the human gene and the 5' end of the mouse GATA3 gene. We show that the
human GATA3 gene contains six exons distributed over 17 kb of DNA. The two human
GATA3 zinc fingers are encoded by two separate exons highly conserved with those
of GATA1, but no other structural homologies between these two genes can be
found. The human and mouse GATA3 transcription units start at a major initiation
site. The promoter sequence analysis of these two genes revealed that they are
embedded within a CpG island and share structural features often found in the
promoters of housekeeping genes. Finally, we show that a DNA fragment containing
the human GATA3 transcription unit, 3 kb upstream from the initiation site and 4
kb downstream from the polyadenylation site, displays T-cell specificity.

PMID: 8088776 [PubMed - indexed for MEDLINE]


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