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bcl-2 Suppresses Expression of p21^WAF1/CIP1 in Breast Epithelial Cells¹

Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201

The tumor suppressor gene p53 regulates G₁ checkpoint prior to the initiation of DNA synthesis, which can either induce G₁ arrest or signal 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, suggesting that bcl-2 interferes with an essential signaling molecule involved in the apoptotic cell death pathway. Although the bcl-2 protein is shown to be overexpressed in many types of human tumor including breast cancer, its biochemical or pathological consequences are poorly understood. To determine the effects of bcl-2 overexpression on apoptosis and transformation of breast epithelial cells and to investigate whether bcl-2 interferes with the p53 pathway, we introduced the bcl-2 expression vector into MCF10A cells, which were derived from diploid human breast epithelial cells containing the wild-type p53 gene. Overexpression of bcl-2 prevented free radical-induced apoptosis and induced a partially transformed phenotype in MCF10A cells. Although overexpression of bcl-2 did not affect the expression of the p53 gene, p53-dependent gene transcription such as p21^WAF1/CIP1 was suppressed. These results suggest that bcl-2 may inhibit p53 functional activity and is involved in the regulation of an early commitment step either to proliferate or suicide.

¹ This work was supported by a fund from the Pathology Department, a Research Stimulation Grant, and American Cancer Society Grant (IRG-162H) (to H-R. C. K.).

² To whom requests for reprints should be addressed, at Department of Pathology, Wayne State University School of Medicine, 540 East Canfield Avenue, Detroit, MI 48201. Phone: (313) 577-2407 or (313) 577-0193; Fax: (313) 577-0057.

Received 5/19/95. Accepted 8/30/95.

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