Mü llerian inhibiting substance (MIS), MIS,1 a member of the TGF-␤ family of hormones, causes regression of the epithelial-mesenchymal unit of the Mü llerian duct in the embryonic male urogenital ridge. In females the Mü llerian duct autonomously differentiates into the uterus, Fallopian tubes, and upper vagina (1). The Mü llerian ducts of both male and female embryos are responsive to MIS only during a critical period in development after which they lose sensitivity (1, 2). However, MIS is produced at high levels by Sertoli cells of the testis even after the regression of the Mü llerian duct, decreases at adolescence, and is produced throughout adult life. In females, it is synthesized by postnatal granulosa cells of the ovary and can be detected in the female serum until menopause (3, 4). Cleavage of MIS by a kex-like enzyme is required to manifest MIS activity since a noncleavable mutant is devoid of biological function (5).The MIS type II receptor gene, a highly conserved single transmembrane serine threonine kinase that is homologous to members of the TGF-␤ family of type II receptors, encodes a 2.0-kilobase mRNA (6 -8). It is expressed at high levels in the Mü llerian duct, Sertoli cells, and granulosa cells of the embryonic and adult gonads and in the uterus (8). The developmental significance of the MIS type II receptor was demonstrated in MIS type II receptor null male mice, which develop normally but have a persistent Mü llerian duct that forms a uterus and oviducts; this phenotype resembles that of MIS ligand-deficient mice (9 -11). Female MIS type II receptor or MIS ligand-deficient mice are normal and fertile as young adults.The detection of MIS in the serum of males and females even after the regression and differentiation of the Mü llerian duct (3, 4) suggests that MIS might be a multifunctional hormone. MIS is a negative regulatory factor in fetal rat lung maturation, where it inhibits the production of pulmonary surfactant both in vitro and in vivo (12, 13). MIS also inhibits oocyte meiosis in vitro (14,15). The presence of MIS type II receptor in non-Mü llerian tissues such as the ovary, lung, and Leydig cells of the testis (16 -18) and the occurrence of Leydig cell hyperplasia and Leydig cell tumors in receptor null male mice (11) also suggest that the biological action of MIS is not limited to the Mü llerian duct. Furthermore, MIS has been shown to inhibit the growth of tumor cells in vitro and in vivo (19 -22). Masiakos et al. (17), using ovarian epithelial cells derived from the ascites of ovarian cancer patients, correlated MIS type II receptor expression with MIS-mediated growth inhibition. Furthermore, exogenous MIS has been shown to inhibit metastases of the ocular melanoma cell line OM431 (23) and to block the growth of the vulvar epidermoid carcinoma cell line A431 and the OM431 cell line in vivo (21,24).Expression of MIS-related proteins including TGF-␤, activin, inhibin, and BMP ligands and their receptors has been demonstrated in human breast cancer cell lines and in breast cancer ...

Mü llerian inhibiting substance (MIS), a transforming growth factor-␤ family member, causes regression of the Mü llerian 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 MISmediated 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 G 1 phase 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 familyregulated 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.MIS, 1 a member of the TGF-␤ family of hormones, induces regression of the epithelial-mesenchymal unit of the Mü llerian duct in the embryonic urogenital ridge in males. In the absence of MIS, differentiation of the Mü llerian duct into the uterus, fallopian tubes, and upper vagina in female embryos occurs autonomously (1). The 140-kDa MIS homodimer is enzymatically cleaved into two distinct fragments. The carboxylterminal fragment composed of a dimer with subunits of M r 12,500 retains bioactivity, whereas a noncleavable mutant is devoid of biological function (2). MIS is produced at high levels by Sertoli cells of the testis even after the regression of the Mü llerian duct and decreases at adolescence. In females, it is synthesized by granulosa cells of the ovary. Measurement of circulating serum MIS levels in females indicates that MIS in females is produced postnatally, increases at the onset of puberty, and is undetectable at menopause (3, 4). It is hypothesized that binding of MIS ligand to the MIS type II receptor, a serine threonine kinase (5-7), leads to heterodimerization with a type I receptor, initiating a signaling cascade.The MIS type II receptor gene contains 11 exons and encodes a 63-kDa protein, which is expressed at very high levels in the uterus, testis, and ovary (5-7). Male mice that lack both alleles of the MIS type II receptor have a persistent Mü llerian duct, which differentiates into a uterus and oviducts, a phenotype reminiscent of MIS ligand null mice (8). Imbeaud et al. (9) have identified MIS type II receptor mutations in male patients with Persistent Mü llerian Duct syndrome, which reaffirms the developmental significance of its expression in humans. Transgenic female mice that overexpress MIS ligand, demonstrate complete ablation of the ovary, along wit...

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