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.

以前的基因靶向研究表明，Bim是一种仅限于BH3的死亡激活剂，而p27^lt；KIP1&gt；是一种周期蛋白依赖的激酶抑制物，可以调节体内的细胞总数。细胞因子主要通过负性调节Bim和p27mRNAs的稳态水平而参与这一过程。我们发现了一种新的机制，通过热休克相关蛋白70(Hsc70)的活性，细胞因子介导的转录后调控Bim和p27 mRNA水平，通过与3‘-非翻译区的富含AU元件(Ares)结合来增强特定mRNAs的稳定性。Hsc70的RNA结合潜力受辅伴蛋白调节，包括BAG-4(也称为SODD)、CHIP、HIP和Hsp40。下调Bim和p27的细胞因子通过RAS激活的信号通路发挥作用，而RAS激活的信号通路反过来又控制这些辅助伴侣的表达或功能。因此，细胞暴露于细胞因子，最终导致Bim和p27mRNAs的不稳定，促进细胞分裂和存活。分子伴侣/辅助分子伴侣复合体在控制信使核糖核酸稳定性方面的这一出人意料的作用似乎对造血和白血病的发生至关重要。

项目成果

Regulation of annexin II by cytokine-initiated signaling pathways and E2A-HLF oncoprotein

• DOI: 10.1182/blood-2003-09-3022
• 发表时间: 2004-04-15
• 期刊: BLOOD
• 影响因子: 20.3
• 作者: Matsunaga, T;Inaba, T;Kurosawa, H
• 通讯作者: Kurosawa, H

Hyperactivation of the RAS signaling pathway in myelodysplastic syndrome with AML1/RUNX1 point mutations

• DOI: 10.1038/sj.leu.2404136
• 发表时间: 2006-04-01
• 期刊: LEUKEMIA
• 影响因子: 11.4
• 作者: Niimi, H;Harada, H;Kimura, A
• 通讯作者: Kimura, A

Roles of Bim in apoptosis of normal and Bcr-Abl-expressing hematopoietic progenitors

• DOI: 10.1128/mcb.24.14.6172-6183.2004
• 发表时间: 2004-07-01
• 期刊: MOLECULAR AND CELLULAR BIOLOGY
• 影响因子: 5.3
• 作者: Kuribara, R;Honda, H;Inaba, T
• 通讯作者: Inaba, T

Cytokine-mediated cell survival

• DOI: 10.1532/ijh97.04093
• 发表时间: 2004-10-01
• 期刊: INTERNATIONAL JOURNAL OF HEMATOLOGY
• 影响因子: 2.1
• 作者: Inaba, T

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.