Mammalian unfolded protein response inhibits cyclin D1 translation and cell-cycle progression.
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.
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
J W
JW
Brewer
L M
LM
Hendershot
C J
CJ
Sherr
J A
JA
Diehl
D016475:3T3 Cells; D000818:Animals; D002453:Cell Cycle / Q000235:genetics*; D019925:Cyclin A / Q000378:metabolism; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D005434:Flow Cytometry; D016193:G1 Phase / Q000235:genetics; D005786:Gene Expression Regulation; D051379:Mice; D014176:Protein Biosynthesis; D017510:Protein Folding; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D014415:Tunicamycin / Q000494:pharmacology
D019925:Cyclin A; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D014415:Tunicamycin; D019938:Cyclin D1; D018844:Cyclin-Dependent Kinases