Bypass of abnormal MDM2 inhibition of p53-dependent growth suppression.
Oncoprotein MDM2 inhibits p53-dependent cell cycle arrest and apoptosis. MDM2-overexpressing human cancer cell lines (n = 3) were found to be resistant to growth inhibition after infection by p53-expressing adenovirus (Ad-p53), as compared to low MDM2-expressing tumors (n = 3), in vitro. The growth of MDM2-overexpressing tumors, however, was inhibited by p21-expressing adenovirus (Ad-p21) infection, and the cyclin-dependent kinase-inhibitory region of p21 was sufficient to bypass the MDM2-p53 feedback loop. The phosphorylation state of Rb correlated with the response to either p53 or p21 gene therapy. MDM2-overexpressing cancer cells infected by Ad-p21 also developed a quiescent large-cell morphology. The results suggest that MDM2-mediated resistance to p53 may be bypassed by p21 and that the Rb phosphorylation state may predict the effects on growth after Ad-p53 or Ad-p21 infection.
Meng
R D
RD
Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Shih
H
H
Prabhu
N S
NS
George
D L
DL
el-Deiry
W S
WS
D000256:Adenoviridae / Q000235:genetics; D002455:Cell Division; D002470:Cell Survival; D016158:Genes, p53 / Q000502:physiology*; D015316:Genetic Therapy; D006801:Humans; D009369:Neoplasms / Q000628:therapy*; D009687:Nuclear Proteins; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2; D016160:Retinoblastoma Protein / Q000378:metabolism; D014407:Tumor Cells, Cultured
D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2