1: J Biol Chem. 2005 Apr 1;280(13):13163-70. Epub 2005 Jan 25. 

GATA transcription factors inhibit cytokine-dependent growth and survival of a
hematopoietic cell line through the inhibition of STAT3 activity.

Ezoe S, Matsumura I, Gale K, Satoh Y, Ishikawa J, Mizuki M, Takahashi S,
Minegishi N, Nakajima K, Yamamoto M, Enver T, Kanakura Y.

Department of Hematology/Oncology, Osaka University Graduate School of Medicine,
2-2, Yamada-oka, Suita, Osaka 565-0871, Japan.

Although GATA-1 and GATA-2 were shown to be essential for the development of
hematopoietic cells by gene targeting experiments, they were also reported to
inhibit the growth of hematopoietic cells. Therefore, in this study, we examined
the effects of GATA-1 and GATA-2 on cytokine signals. A tamoxifen-inducible form
of GATA-1 (GATA-1/ERT) showed a minor inhibitory effect on interleukin-3
(IL-3)-dependent growth of an IL-3-dependent cell line Ba/F3. On the other hand,
it drastically inhibited TPO-dependent growth and gp130-mediated growth/survival
of Ba/F3. Similarly, an estradiol-inducible form of GATA-2 (GATA-2/ER) disrupted
thrombopoietin (TPO)-dependent growth and gp130-mediated growth/survival of
Ba/F3. As for this mechanism, we found that both GATA-1 and GATA-2 directly
bound to STAT3 both in vitro and in vivo and inhibited its DNA-binding activity
in gel shift assays and chromatin immunoprecipitation assays, whereas they
hardly affected STAT5 activity. In addition, endogenous GATA-1 was found to
interact with STAT3 in normal megakaryocytes, suggesting that GATA-1 may inhibit
STAT3 activity in normal hematopoietic cells. Furthermore, we found that GATA-1
suppressed STAT3 activity through its N-zinc finger domain. Together, these
results suggest that, besides the roles as transcription factors, GATA family
proteins modulate cytokine signals through protein-protein interactions, thereby
regulating the growth and survival of hematopoietic cells.

PMID: 15673499 [PubMed - indexed for MEDLINE]


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2: Blood. 1996 Oct 15;88(8):3074-82. 

The biologic properties of recombinant human thrombopoietin in the proliferation
and megakaryocytic differentiation of acute myeloblastic leukemia cells.

Matsumura I, Kanakura Y, Kato T, Ikeda H, Horikawa Y, Ishikawa J, Kitayama H,
Nishiura T, Tomiyama Y, Miyazaki H, Matsuzawa Y.

Second Department of Internal Medicine, Osaka University Medical School, Japan.

Thrombopoietin (TPO) is implicated as a primary regulator of megakaryopoiesis
and thrombopoiesis. However, the biologic effects of TPO on human acute
myeloblastic leukemia (AML) cells are largely unknown. To determine if
recombinant human (rh) TPO has proliferation-supporting and
differentiation-inducing activities in AML cells, 15 cases of AML cells that
were exclusively composed of undifferentiated leukemia cells and showed growth
response to rhTPO in a short-term culture (72 hours) were subjected to long-term
suspension culture with or without rhTPO. Of 15 cases, rhTPO supported
proliferation of AML cells for 2 to 4 weeks in 4 cases whose
French-American-British subtypes were M0, M2, M4, and M7, respectively. In
addition to the proliferation-supporting activity, rhTPO was found to induce AML
cells to progress to some degree of megakaryocytic differentiation at both
morphologic and surface-phenotypic level in 2 AML cases with M0 and M7 subtypes.
The treatment of AML cells with rhTPO resulted in rapid tyrosine phosphorylation
of the TPO-receptor, c-mpl, and STAT3 in all of cases tested. By contrast, the
expression of erythroid/megakaryocyte-specific transcription factors (GATA-1,
GATA-2, and NF-E2) was markedly induced or enhanced in only 2 AML cases that
showed megakaryocytic differentiation in response to rhTPO. These results
suggested that, at least in a fraction of AML cases, TPO could not only support
the proliferation of AML cells irrespective of AML subtypes, but could also
induce megakaryocytic differentiation, possibly through activation of GATA-1,
GATA-2, and NF-E2.

PMID: 8874206 [PubMed - indexed for MEDLINE]


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