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 stre ss response that up-regulates the expression of ER chaperones, while coordi nately repressing overall protein synthesis and causing cell-cycle arrest. Activation of this unfolded protein response (UPR) in mouse NIH 3T3 fibrobl asts with the glycosylation inhibitor tunicamycin led to a decline in cycli n 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 t he extracellular signal-activated protein kinases ERK1 and ERK2 or the leve l of cyclin D1 mRNA until much later in the response. Therefore, the UPR tr iggers a signaling pathway that blocks cyclin D1 translation despite contin uous mitogenic stimulation. Enforced overexpression of cyclin D1 in tunicam ycin-treated cells maintained cyclin D- and E-dependent kinase activities a nd 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 checkpo int control that prevents cell-cycle progression until homeostasis is resto red.