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J. Biol. Chem., Vol. 280, Issue 13, 13163-13170, April 1, 2005

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GATA Transcription Factors Inhibit Cytokine-dependent Growth and Survival of a Hematopoietic Cell Line through the Inhibition of STAT3 Activity^*

Sachiko Ezoe, Itaru Matsumura, Karin Gale¶, Yusuke Satoh, Jun Ishikawa, Masao Mizuki, Satoru Takahashi||, Naoko Minegishi**, Koichi Nakajima, Masayuki Yamamoto, Tariq Enver¶¶, and Yuzuru Kanakura

From the Department of Hematology/Oncology, Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita, Osaka 565-0871, Japan, the ^¶Section of Gene Function and Regulation, Chester Beatty Laboratories, Institute of Cancer Research, Fulham Road, London SW3 6JB, United Kingdom, the ^||Division of Anatomy and Embryology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan, the ^**Department of Molecular Diagnostics, Tohoku University School of Medicine, 2-1 Seiryotyo Aobaku, Sendai 980-8575, Japan, the Department of Immunology, Osaka City University Graduate School of Medicine,1-4-3, Asahityo, Abenoku, Osaka 545-8585, Japan, the Center for Tsukuba Advanced Research Alliance and Institute of Basic Medical Institute, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-0006, Japan, and the ^¶¶MRC Molecular Haematology Unit, Weatherall Institute for Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom

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.

Received for publication, November 30, 2004 , and in revised form, January 19, 2005.

^* This work was supported by grants from the Ministry of Education, Science, and Culture of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Tel.: 81-6-6879-3871; Fax: 81-6-6879-3879; E-mail: matumura{at}bldon.med.osaka-u.ac.jp.

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