Mullerian inhibiting substance inhibits ovarian cell growth through an Rb-independent mechanism

Mullerian inhibiting substance (MIS), a transforming growth factor-beta fam ily member, causes regression of the Mullerian duct in male embryos. MIS ov erexpression in transgenic mice ablates the ovary, and MIS inhibits the gro wth of ovarian cancer cell lines in vitro, suggesting a key role for this h ormone in postnatal development of the ovary. This report describes a mecha nism for MIS-mediated growth inhibition in both a human epithelial ovarian cancer cell line and a cell line derived from normal ovarian surface epithe lium, which is the origin of human epithelial ovarian cancers, MIS-treated cells accumulated in the G(1) phase of the cell cycle and subsequently unde rwent apoptosis. MIS up-regulated the cyclin-dependent kinase inhibitor pie 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 gro wth. These findings demonstrate that pig is required for MIS-mediated growt h inhibition in ovarian epithelial cells and tumor cells and suggest that u p-regulation of E2F1 also plays a role in this process.