Analysis of expression control of the Bim gene.

Bim 基因的表达控制分析。

• 批准号: 16390279
• 负责人: INABA Toshiya
• 金额: $ 8.51万
• 依托单位: HIROSHIMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390279/
• 关键词: mRNA stability; cytokine; heat shock protein; co-chaperone; Bim; p27; Hsc70; CML; apoptosis; mRNA安定性制御

Previous gene-targeting studies indicated that Bim, a BH3-only death activator, and p27^<KIP1>, a cyclin-dependent kinase inhibitor, regulate total cell number in the body. Cytokines contribute to this process primarily by negatively regulating the steady-state levels of Bim and p27 mRNAs. We discovered a novel mechanism for cytokine-mediated post-transcriptional regulation of Bim and p27 mRNA levels via the activity of Heat shock cognate protein 70 (Hsc70), which enhances the stability of specific mRNAs by binding to AU-rich elements (AREs) in their 3'-untranslated regions. The RNA-binding potential of Hsc70 is regulated by co-chaperones, including Bag-4 (also SODD), CHIP, Hip and Hsp40. Cytokines that down-regulate Bim and p27 operate via Ras-activated signaling pathways, which in turn control the expression or function of these co-chaperones. Thus, exposure of cells to cytokines ultimately leads to the destabilization of Bim and p27 mRNAs and the promotion of cell division and survival. This unanticipated role for a chaperone/co-chaperone complex in the control of mRNA stability appears to be critical for hematopoiesis and leukemogenesis.

先前的基因靶向研究表明，仅BH3死亡激活剂BIM和依赖细胞周期蛋白依赖性激酶抑制剂的P27^<kip1>调节体内的总细胞数。细胞因子主要通过负调节BIM和P27 mRNA的稳态水平来促进这一过程。我们通过热休克同源蛋白70（HSC70）的活性发现了细胞因子介导的BIM和P27 mRNA水平的转录后调节的新机制，从而增强了特定mRNA的稳定性，通过与Au-rich元素（ARES）结合在其3'-Untranslated地区。 HSC70的RNA结合电位受共同伴侣的调节，包括Bag-4（也是SODD），芯片，髋关节和HSP40。下调BIM和p27的细胞因子通过RAS激活的信号通路运行，进而控制这些共伴侣的表达或功能。因此，细胞暴露于细胞因子最终导致BIM和p27 mRNA的稳定以及促进细胞分裂和生存。伴侣/共伴侣复合物在mRNA稳定性中的这种意外作用对于造血和白血病发生似乎至关重要。

项目成果

The Adenovirus E1A and E1B19K genes provide a helper function for transfection-based AAV vector production.

腺病毒 E1A 和 E1B19K 基因为基于转染的 AAV 载体生产提供辅助功能。

• 发表时间: 2004
• 期刊: J.Gen.Virol. 85
• 作者: Matsushita T.;et al.
• 通讯作者: et al.