Journal of Biological Chemistry
Volume 275, Issue 47, 24 November 2000, Pages 37101-37109
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MECHANISMS OF SIGNAL TRANSDUCTION
Müllerian Inhibiting Substance Inhibits Ovarian Cell Growth through an Rb-independent Mechanism*

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Müllerian inhibiting substance (MIS), a transforming growth factor-β family member, causes regression of the Müllerian duct in male embryos. MIS overexpression in transgenic mice ablates the ovary, and MIS inhibits the growth of ovarian cancer cell lines in vitro, suggesting a key role for this hormone in postnatal development of the ovary. This report describes a mechanism for MIS-mediated growth inhibition in both a human epithelial ovarian cancer cell line and a cell line derived from normal ovarian surface epithelium, which is the origin of human epithelial ovarian cancers. MIS-treated cells accumulated in the G1phase of the cell cycle and subsequently underwent apoptosis. MIS up-regulated the cyclin-dependent kinase inhibitor p16 through an MIS type II receptor-mediated mechanism and inhibited growth in the absence of detectable or inactive Rb protein. Prolonged treatment with MIS down-regulated the Rb-related protein p130 and increased the Rb family-regulated transcription factor E2F1, overexpression of which inhibited growth. These findings demonstrate that p16 is required for MIS-mediated growth inhibition in ovarian epithelial cells and tumor cells and suggest that up-regulation of E2F1 also plays a role in this process.

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Published, JBC Papers in Press, August 24, 2000, DOI 10.1074/jbc.M005701200

*

This work was supported by Grant IRG-173H from the American Cancer Society (to S. M.) and a Breast Cancer Research Grant from the Massachusetts Department of Public Health (to S. M.), by National Cancer Institute (NCI)/National Institutes of Health (NIH) Training Grant T32-CA-71345 in Cancer Biology (to D. L. S.), and a Resident Research Award from the American College of Surgeons (to D. L. S.), and by Grants HD32112 and CA17393 from the NICHD/NIH and NCI/NIH (to P. K. D.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.