Mammalian Unfolded Protein Response Inhibits Cyclin D1 Translation and Cell-Cycle Progression

• Published in: Proceedings of the National Academy of Sciences - PNAS 1999-07, Vol.96 (15), p.8505-8510
• Main Authors: Brewer, Joseph W., Hendershot, Linda M., Sherr, Charles J., Diehl, J. Alan
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; Antibodies; Biological Sciences; Cell Cycle - genetics; Cells; Cellular biology; Crystallography; Cyclin A - metabolism; Cyclin D1 - biosynthesis; Cyclin D1 - metabolism; Cyclin-Dependent Kinases - metabolism; Cyclins; DNA; Flow Cytometry; G1 Phase - genetics; Gels; Gene Expression Regulation; Interphase; Messenger RNA; Mice; NIH 3T3 cells; Protein Biosynthesis; Protein Folding; Protein Synthesis Inhibitors - pharmacology; Proteins; RNA, Messenger - metabolism; Signal Transduction; Tunicamycin - pharmacology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.96.15.8505

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 G1 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.