p53-Independent Down-Regulation of Mdm2 in Human Cancer Cells Treated with Abriamycin

摘要

Mdm2 is a nuclear phosphoprotein which functions as a negative feedback regulator of the p53 tumor suppressor gene. In this study,we investigated the alteration of Mdm2 and p53 in three human cancer cell ines containing either a wild-type or mutant p53 gene after treatment with Adriamycin (doxorubicin,ADR).a DNA damaging agent.We found that human breast cancer MCF-7 cells contining wild-type p53 were much more susceptible to ADR compared to human breast cancer MDA-MB-231 and human prostate cancer Du-145 cells which contatin mutant p53.ADR resulted in a significant dose-dependent accumulation of p53 protein in MCF-7 cells, whereas little or no influence was observed on p53 protein of the two mutant mutant p53 cell lines.However,a significant down-regulation of Mdm2 at protein and mRNA levels was observed in these three cell lines following ADR treatment. Moreover,the decrease of Mdm2 was in both a dose- and time-dependent manner. It is interestingly noted that 5 #mu#M is a critical dose for significant down-regulation of the Mdm2 protein.Selected proteasome inhibitors did not rescue the ADR-caused decline in the expression of Mdm2 protein.Therefore, our present results reveal that ADR can induce a down-regulation of Mdm2 via a p53-independent pathway in human cancer cells and the ubiquition-proteasome degradation mechanism may not be involved in the decreased expression of Mdm2 protein.