Cytokines direct the regulation of Bim mRNA stability by heat-shock cognate protein 70
Cytokines direct the regulation of Bim mRNA stability by heat-shock cognate protein 70
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DOI：
10.1016/j.molcel.2006.12.007
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发表时间：
2007-01-12
期刊：
影响因子：
16
通讯作者：
Inaba, Toshiya
中科院分区：
文献类型：
--
作者：
Matsui, Hirotaka;Asou, Hiroya;Inaba, Toshiya
以前的基因靶向研究表明，Bim是一种仅有BH3的死亡激活剂，调节血细胞总数。细胞因子通过负性调节Bim mRNA的稳态水平而参与这一过程。在这里，我们提出了细胞因子介导的热休克相关蛋白70(Hsc70)对Bim mRNA转录后调控的分子机制，Hsc70与特定mRNAs的3-非翻译区富含AU元件(Ares)结合，并增强其稳定性。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。细胞因子通过激活RAS通路来调节这些辅伴侣蛋白的表达或功能。因此，细胞暴露于细胞因子，最终导致Bim mRNA的不稳定，促进细胞存活。分子伴侣/辅分子伴侣复合体在mRNA稳定性中的这一出人意料的作用似乎对造血和白细胞的生成至关重要。
Previous gene-targeting studies indicated that Bim, a BH3-only death activator, regulates total blood cell number. Cytokines contribute to this process by negatively regulating steady-state levels of Bim mRNA. Here we present a molecular mechanism for cytokine-mediated posttranscriptional regulation of Bim mRNA by heat-shock cognate protein 70 (Hsc70), which binds to AU-rich elements (AREs) in the 3-untranslated region of specific mRNAs and enhances their stability. The RNA binding potential of Hsc70 is regulated by cochaperones including Bag-4 (also SODD), CHIP, Hip, and Hsp40. Cytokines regulate the expression or function of these cochaperones by activating Ras pathways. Thus, exposure of cells to cytokines; ultimately leads to destabilization of Bim mRNA and promotion of cell survival. This unanticipated role of a chaperone/cochaperone complex in mRNA stability appears to be critical for hematopoiesis and leukernogenesis.