Cytokines direct the regulation of Bim mRNA stability by heat-shock cognate protein 70.
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 leukemogenesis.
Matsui
Hirotaka
H
Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan.
Asou
Hiroya
H
Inaba
Toshiya
T
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D002470:Cell Survival / Q000187:drug effects; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D050883:HSC70 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000378:metabolism; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D039122:Poly(A)-Binding Protein I / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D039603:Eukaryotic Initiation Factor-4G; C000630986:HNRNPD protein, human; D050883:HSC70 Heat-Shock Proteins; D050956:HSP40 Heat-Shock Proteins; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; C000630987:Hnrpd protein, mouse; D007377:Interleukin-3; D008565:Membrane Proteins; D039122:Poly(A)-Binding Protein I; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D018631:ras Proteins