title: GATA transcription factors inhibit cytokine-dependent growth and survival of a hematopoietic cell line through the inhibition of STAT3 activity.
abstract: 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.
authors.affiliation: Department of Hematology/Oncology, Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Ezoe
authors.forename: Itaru
authors.initials: I
authors.lastname: Matsumura
authors.forename: Karin
authors.initials: K
authors.lastname: Gale
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Satoh
authors.forename: Jun
authors.initials: J
authors.lastname: Ishikawa
authors.forename: Masao
authors.initials: M
authors.lastname: Mizuki
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Naoko
authors.initials: N
authors.lastname: Minegishi
authors.forename: Koichi
authors.initials: K
authors.lastname: Nakajima
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Tariq
authors.initials: T
authors.lastname: Enver
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Kanakura
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D001854:Bone Marrow Cells / Q000166:cytology; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D050981:Erythroid-Specific DNA-Binding Factors; D004958:Estradiol / Q000378:metabolism; D005434:Flow Cytometry; D050982:GATA1 Transcription Factor; D050989:GATA2 Transcription Factor; D005982:Glutathione Transferase / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007377:Interleukin-3 / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D050796:STAT3 Transcription Factor; D013629:Tamoxifen / Q000494:pharmacology; D013926:Thrombopoietin / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*
chemical_list: D016207:Cytokines; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C494689:Gata1 protein, mouse; C494712:Gata2 protein, mouse; D007377:Interleukin-3; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D013629:Tamoxifen; D004958:Estradiol; D013926:Thrombopoietin; D008156:Luciferases; D005982:Glutathione Transferase