P53-DEPENDENT INDUCTION OF APOPTOSIS BY PROTEASOME INHIBITORS

Proteolysis by the ubiquitin/proteasome pathway controls the intracell ular levels of a number of proteins that regulate cell proliferation a nd cell cycle progression, To determine whether this pathway of protei n turnover was also linked to apoptosis, we treated Rat-1 and PC12 cel ls with specific proteasome inhibitors. The peptide aldehydes PSI and MG115, which specifically inhibit the chymotrypsin-like activity of th e proteasome, induced apoptosis of both cell types, In contrast, apopt osis was not induced by inhibitors of lysosomal proteases or by an alc ohol analog of PSI. The tumor suppressor p53 rapidly accumulated in ce lls treated with proteasome inhibitors, as did the p53-inducible gene products p21 and Mdm-2. In addition, apoptosis induced by proteasome i nhibitors was inhibited by expression of dominant-negative p53, wherea s overexpression of wild-type p53 was sufficient to induce apoptosis o f Rat-1 cells in transient transfection assays. Although other molecul es may also be involved, these results suggest that stabilization and accumulation of p53 plays a key role in apoptosis induced by proteasom e inhibitors.