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Role of p53 in Cell Cycle Regulation and Apoptosis following Exposure to Proteasome Inhibitors¹

Department of Radiation Oncology, Division of Cancer Biology, University of Michigan Comprehensive Cancer Center [F. C., D. C., S. A. K., M. L.] and Section of Urology [M. G.], Program in Cellular and Molecular Biology [M. L.], University of Michigan Medical School, Ann Arbor, Michigan 48109-0396

Abstract

In this study, we explored what effect inhibitors of the 26S proteasome have on cell cycle distribution and induction of apoptosis in human skin fibroblasts and colon cancer cells differing in their p53 status. We found that proteasome inhibition resulted in nuclear accumulation of p53. This was surprising because it is thought that the degradation of p53 is mediated by cytoplasmic 26S proteasomes. Nuclear accumulation of p53 was accompanied by the induction of both p21^WAF1 mRNA and protein as well as a decrease in cells entering S phase. Interestingly, cells with compromised p53 function showed a marked increase in the proportion of cells in the G₂-M phase of the cell cycle and an attenuated induction of apoptosis after proteasome inhibition. Taken together, our results suggest that proteasome inhibition results in nuclear accumulation of p53 and a p53-stimulated induction of both G₁ arrest and apoptosis.

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