Analysis on the effects of GATA transcription factors on cell cycle regulatoy molecules in hematopoietic cells

GATA转录因子对造血细胞细胞周期调节分子的影响分析

• 批准号: 14570978
• 负责人: MATSUMURA Itaru
• 金额: $ 2.62万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570978/
• 关键词: GATA-1; GATA-2; c-myc; p21WAF1; p27Kip1; STAT3; Ras; Ras; c-Myc; 細胞周期; 細胞増殖

In this study, we have analyzed the effects of GATA transcription factors on the expression and function of cell cycle regulatory molecules in hematopoietic cells and got the results as follows:1. A4-HT-inducible from of GATA-2/ERT inhibited the IL-3-dependent growth of BaIF3, 32D, and FDC-P1 cells arid cytokine-dependent growth of normal hematopoletic stem/progenitor cells.2. GATA-2/ERT suppressed the expression of c-myc and CDK4 mRNA and accumulated p21WAF1 and p27Kip1 proteins, whereas it did not influence the mRNA expression levels of pl6INK4A, p15INK4B, p21WAF1 or p27Kip1.3. GATA-2 inhibited ubiquitin/proteasome-dependent degradation of p21WAF1 and p27Kip1 and induced their accumulation by repressing the expression of Skp2 and Cull, both of which are components of the ubiquitin ligase for p21WAF1 and p27Kip1.4. The amount of GATA-2 protein declined in hematopoletic stem/progenitor cells that were promoted to enter cell cycle by the stimulation with cytokines.5. GATA-1 directly bound to STAT3 and inhibited its DNA-binding activity.6. GATA-1 inhibited oncogenic Ras (H-RasG12V)-induced MEKK1 activation, thereby suppressed H-RasG12V-dependent growth and survival of Ba/F3 cells.These results suggest that GATA transcription factors may suppressthe cytokine signaling and modulate the expression of p21WAF1 and p27Kip1, thereby inhibiting cell cycle progression of hematopoietic cells.

在本研究中，我们分析了GATA转录因子对造血细胞细胞周期调控分子表达和功能的影响，得到如下结果：1.GATA-2/ERT诱导的A4-HT抑制BaIF3、32D和FDC-P1细胞依赖IL-3的生长和正常造血干/祖细胞的细胞因子依赖的生长。GATA-2/ERT抑制c-myc和CDK4基因的表达，抑制p21WAF1和p27Kip1蛋白的表达，但不影响pl6INK4A、p15INK4b、p21WAF1和p27Kip1.3的基因表达水平。GATA-2抑制依赖泛素/蛋白酶体的p21WAF1和p27Kip1的降解，并通过抑制p21WAF1和p27Kip1.4的泛素连接酶Skp2和cull的表达而诱导它们的积聚。细胞因子刺激促进造血干/祖细胞进入细胞周期的GATA-2蛋白含量下降。GATA-1直接与STAT3结合并抑制其DNA结合活性。GATA-1抑制致癌RAS(H-RasG12V)诱导的MEKK1激活，从而抑制H-RasG12V依赖的细胞生长和存活，提示GATA转录因子可能抑制细胞因子信号转导，调节p21WAF1和p27Kip1的表达，从而抑制造血细胞的细胞周期进程。

项目成果

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Matsumura I 等人：“E2F1 和 c-Myc 在细胞生长和存活调节中的作用”细胞周期。

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