p53-dependent apoptosis induced by proteasome inhibition in mammary epithelial cells

We have examined the effects of inhibition of the 26S proteasome in a murin e mammary cell line, KIM-2 cells using the peptide aldehyde inhibitor MG132 , These studies have demonstrated a clear requirement for proteasome functi on in cell viability. Induction of apoptosis was observed following MG132 t reatment in KIM-2 cells and this death was shown to be dependent on the cel l actively traversing the cell cycle. KIM-2 cells were generated using a te mperature sensitive T-antigen (Tag) and studies at the permissive temperatu re (33 C) have shown that a Tag binding protein was essential for this apop totic response, Studies in two additional cell lines, HC11, which is a mamm ary epithelial cell line carrying mutant p53 alleles and p53 null ES cells suggest that p53 is actively required for the apoptosis induced as a conseq uence of proteasome inhibition, These results suggest a pivotal role for th e 26S proteasome degradation pathway in progression through the cell cycle in proliferating cells.