Inhibition of steroidogenesis in Leydig cells by Müllerian-inhibiting substance.
Müllerian-inhibiting substance (MIS), a member of the transforming growth factor-beta family of cytokines that signal through a heteromeric complex of single-transmembrane serine/threonine kinase receptors, is required for Müllerian duct regression and normal reproductive tract development in the male embryo. However, the continued expression of MIS at high levels in males until puberty and its induction in females after birth suggested other roles for MIS. Additionally, Leydig cell development and steroidogenic capacity and ovarian follicle recruitment were abnormal in MIS-knockout or MIS-overexpressing mice. We have shown that MIS inhibits the cAMP-induced expression of cytochrome P450 C17alpha-hydroxylase/C17-20 lyase (Cyp17) mRNA both in vitro and in vivo. Our current efforts are to understand the molecular mechanisms regulating both MIS type II receptor (MISRII) expression and its signaling in rodent Leydig cell lines. MISRII expression in R2C cells requires both steroidogenic factor-1 and an unknown protein to bind to its proximal promoter in the context of 1.6 kb 5'-flanking DNA. When bound by MIS, signaling by the receptor in MA-10 cells blocks the protein kinase A-mediated induction of Cyp17 expression by a cAMP regulatory element-binding protein independent mechanism. We continue to investigate the molecular mechanisms of MISRII expression and possible interactions between MIS-regulated SMAD activation and cAMP signaling. These studies will provide a better understanding of the role played by MIS during postnatal life.
Fynn-Thompson
Eric
E
Pediatric Surgical Research Laboratories, Massachusetts General Hospital and Harvard Medical School, 32 Fruit Street, Boston, MA 02114, USA.
Cheng
Henry
H
Teixeira
Jose
J
D019326:17-alpha-Hydroxyprogesterone / Q000097:blood / Q000378:metabolism; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D054304:Anti-Mullerian Hormone; D045744:Cell Line, Tumor; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D051717:Fushi Tarazu Transcription Factors; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000494:pharmacology / Q000502:physiology*; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D011374:Progesterone / Q000097:blood / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D051381:Rats; D018000:Receptors, Peptide / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta; D015398:Signal Transduction / Q000502:physiology; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics; D054339:Steroidogenic Factor 1; D013256:Steroids / Q000096:biosynthesis*; D013735:Testicular Hormones / Q000494:pharmacology / Q000502:physiology*; D013739:Testosterone / Q000097:blood / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D006063:Chorionic Gonadotropin; D004268:DNA-Binding Proteins; D051717:Fushi Tarazu Transcription Factors; D006023:Glycoproteins; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; D054339:Steroidogenic Factor 1; D013256:Steroids; D013735:Testicular Hormones; D014157:Transcription Factors; C084621:anti-Mullerian hormone receptor; C515058:steroidogenic factor 1, mouse; C515060:steroidogenic factor 1, rat; D015124:8-Bromo Cyclic Adenosine Monophosphate; D013739:Testosterone; D011374:Progesterone; D019326:17-alpha-Hydroxyprogesterone; D054304:Anti-Mullerian Hormone; D000242:Cyclic AMP; D013254:Steroid 17-alpha-Hydroxylase