Analysis of expression control of the Bim gene.

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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.