Role of p53 in cell cycle regulation and apoptosis following exposure to proteasome inhibitors

In this study, we explored what effect inhibitors of the 26S proteasome hav e on cell cycle distribution and induction of apoptosis in human skin fibro blasts and colon cancer cells differing in their p53 status. We found that proteasome inhibition resulted in nuclear accumulation of p53. This was sur prising because it is thought that the degradation of p53 is mediated by cy toplasmic 26S proteasomes. Nuclear accumulation of p53 was accompanied by t he induction of both p21(WAF1) mRNA and protein as well as a decrease in ce lls entering S phase. Interestingly, cells with compromised p53 function sh owed a marked increase in the proportion of cells in the G(2)-M phase of th e cell cycle end an attenuated induction of apoptosis after proteasome inhi bition. Taken together, our results suggest that proteasome inhibition resu lts in nuclear accumulation of p53 and a p53-stimulated induction of both G (1) arrest and apoptosis.