BCL-2 SUPPRESSES EXPRESSION OF P21(WAFL CIPL) IN BREAST EPITHELIAL-CELLS/

The tumor suppressor gene p53 regulates G(1) checkpoint prior to the i nitiation of DNA synthesis, which can either induce G(1) arrest or sig nal apoptosis. The involvement of p53 in apoptosis may also be related to its ability to down-regulate transcription of the bcl-2 gene. The bcl-2 gene product prevents most types of apoptotic cell death, sugges ting that bcl-2 interferes with an essential signaling molecule involv ed in the apoptotic cell death pathway. Although the bcl-2 protein is shown to be overexpressed in many types of human tumor including breas t cancer, its biochemical or pathological consequences are poorly unde rstood. To determine the effects of bcl-2 overexpression on apoptosis and transformation of breast epithelial cells and to investigate wheth er bcl-2 interferes with the p53 pathway, we introduced the bcl-2 expr ession vector into MCF10A cells, which were derived from diploid human breast epithelial cells containing the wild-type p53 gene. Overexpres sion of bcl-2 prevented free radical-induced apoptosis and induced a p artially transformed phenotype in MCF10A cells. Although overexpressio n of bcl-2 did not affect the expression of the p53 gene, p53-dependen t gene transcription such as p21(WAF1/CIP1) was suppressed. These resu lts suggest that bcl-2 may inhibit p53 functional activity and is invo lved in the regulation of an early commitment step either to prolifera te or suicide.