MDM2 AND BAX, DOWNSTREAM MEDIATORS OF THE P53 RESPONSE, ARE DEGRADED BY THE UBIQUITIN-PROTEASOME PATHWAY

Upon activation in response to cellular stress or DNA damage, the p53 tumor suppressor induces the expression of gene products involved in c ell cycle arrest and apoptosis. Using the proteasome-specific inhibito rs, MG132 (N-acetyl-L-leucinyl-L-leucinal-L-leucinal) and lactacystin, here we show that the p53-response proteins, bar and mdma as well as p21, are degraded by the ubiquitin-proteasome pathway in HeLa cells. M G132 also increased expression of the three proteins in cells that lac k p53, showing that stabilization of the p53 response proteins is not due to increased levels of p53 itself, Increases in mdma protein level s by MG132 was accompanied by increases in polyubiquitinated forms of the proteins. Our results indicate that ubiquitin-dependent protein de gradation influences the turnover of downstream targets of p53, theref ore suggesting that the proteasome plays a role in regulating apoptosi s and cell cycle arrest in response to p53.