Mammalian unfolded protein response inhibits cyclin D1 translation and cell-cycle progression

被引:236
作者
Brewer, JW
Hendershot, LM
Sherr, CJ
Diehl, JA
机构
[1] St Jude Childrens Res Hosp, Dept Tumor Cell Biol, Memphis, TN 38105 USA
[2] St Jude Childrens Res Hosp, Howard Hughes Med Inst, Memphis, TN 38105 USA
关键词
endoplasmic reticulum stress; cyclin-dependent kinases;
D O I
10.1073/pnas.96.15.8505
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Alterations in normal protein biogenesis and the resulting accumulation of improperly folded proteins in the endoplasmic reticulum (ER) trigger a stress response that up-regulates the expression of ER chaperones, while coordinately repressing overall protein synthesis and causing cell-cycle arrest. Activation of this unfolded protein response (UPR) in mouse NIH 3T3 fibroblasts with the glycosylation inhibitor tunicamycin led to a decline in cyclin D- and E-dependent kinase activities and to G(1) phase arrest. Cyclin D1 protein synthesis was rapidly inhibited by tunicamycin treatment. However, the drug did not significantly affect the mitogen-dependent activities of the extracellular signal-activated protein kinases ERK1 and ERK2 or the level of cyclin D1 mRNA until much later in the response. Therefore, the UPR triggers a signaling pathway that blocks cyclin D1 translation despite continuous mitogenic stimulation. Enforced overexpression of cyclin D1 in tunicamycin-treated cells maintained cyclin D- and E-dependent kinase activities and kept cells in cycle in the face of a fully activated UPR, Translational regulation of cyclin D1 in response to ER stress is a mechanism for checkpoint control that prevents cell-cycle progression until homeostasis is restored.
引用
收藏
页码:8505 / 8510
页数:6
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