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....

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Bibliographic Details
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
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.96.15.8505