BYPASS OF ABNORMAL MDM2 INHIBITION OF P53-DEPENDENT GROWTH SUPPRESSION

Oncoprotein MDM2 inhibits p53-dependent cell cycle arrest and apoptosi s. MDM2-overexpressing human cancer cell lines (n = 3) were found to b e resistant to growth inhibition after infection by p53-expressing ade novirus (Ad-p53), as compared to low MDM2-expressing tumors (n = 3), i n vitro. The growth of MDM2-overexpressing tumors, however, was inhibi ted by p21-expressing adenovirus (Ad-p21) infection, and the cyclin-de pendent kinase-inhibitory region of p21 was sufficient to bypass the M DM2-p53 feedback loop. The phosphorylation state of Rb correlated with the response to either p53 or p21 gene therapy. MDM2-overexpressing c ancer cells infected by Ad-p21 also developed a quiescent large-cell m orphology. The results suggest that MDM2-mediated resistance to p53 ma y be bypassed by p21 and that the Rb phosphorylation state may predict the effects on growth after Ad-p53 or Ad-p21 infection.