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.