This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Laurich, V. M. Articles by Teixeira, J. Search for Related Content PubMed PubMed Citation Articles by Laurich, V. M. Articles by Teixeira, J.

Müllerian Inhibiting Substance Blocks the Protein Kinase A-Induced Expression of Cytochrome P450 17-Hydroxylase/C_17–20 Lyase mRNA in a Mouse Leydig Cell Line Independent of cAMP Responsive Element Binding Protein Phosphorylation

Pediatric Surgical Research Laboratories (V.M.L., A.M.T., F.H.O., C.P.H., P.K.D., J.T.), Reproductive Endocrine Unit (P.M.S.) Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; and the Division of Reproductive Biology, Department of Gynecology/Obstetrics, Stanford University (A.H.P.), Palo Alto, California 94305

Address all correspondence and requests for reprints to: Jose Teixeira, Ph.D., Pediatric Surgical Research Laboratories/WRN1024, Massachusetts General Hospital, 32 Fruit Street, Boston, Massachusetts 02114. E-mail: teixeira{at}helix.mgh.harvard.edu.

Müllerian inhibiting substance (MIS) is produced by fetal Sertoli cells and causes regression of the Müllerian duct in male fetuses shortly after commitment of the bipotential embryonic gonad to testes differentiation. MIS is also produced by the Sertoli cells and granulosa cells of the adult gonads where it plays an important role in regulating steroidogenesis. We have previously shown that MIS can dramatically reduce testosterone synthesis in Leydig cells by inhibiting the expression of cytochrome P450 17-hydroxylase/C_17–20 lyase (Cyp17) mRNA in vitro and in vivo. To characterize the signal transduction pathway used by MIS to control expression of endogenous Cyp17 in a mouse Leydig cell line, we demonstrate that MIS inhibits both LH- and cAMP-induced expression of Cyp17 at concentrations as low as 3.5 nM and for as long as 18 h. The induction of steroidogenic acute regulatory protein (StAR) mRNA by cAMP, however, was slightly increased by addition of MIS. Protein kinase A (PKA) inhibition with H-89 blocked Cyp17 mRNA induction, suggesting that MIS interferes with the PKA signal transduction pathway. Inhibition of Cyp17 induction was not seen with added U0126, and wortmannin inhibited the induction incompletely. In addition, phosphorylation of the cAMP responsive element binding protein (CREB) was not detected following 50 µM cAMP exposure, a concentration sufficient for Cyp17 mRNA induction. Moreover, CREB phosphorylation, which was observed with addition of 500 µM cAMP, was not inhibited by coincubation with MIS. Taken together, these results suggest that cAMP induces expression of Cyp17 by a PKA-mediated mechanism and that this induction, which is inhibited by MIS signal transduction, does not require CREB activity, and is distinct from that used to induce steroidogenic acute regulatory protein expression.

This article has been cited by other articles:

				R. Homburg Androgen circle of polycystic ovary syndrome Hum. Reprod., July 1, 2009; 24(7): 1548 - 1555. [Abstract] [Full Text] [PDF]

				P. R. Manna, M. T. Dyson, Y. Jo, and D. M. Stocco Role of Dosage-Sensitive Sex Reversal, Adrenal Hypoplasia Congenita, Critical Region on the X Chromosome, Gene 1 in Protein Kinase A- and Protein Kinase C-Mediated Regulation of the Steroidogenic Acute Regulatory Protein Expression in Mouse Leydig Tumor Cells: Mechanism of Action Endocrinology, January 1, 2009; 150(1): 187 - 199. [Abstract] [Full Text] [PDF]

				Y.-C. Chen, R. K Cochrum, M. T Tseng, D. T Ghooray, J. P Moore, S. J Winters, and B. J Clark Effects of CDB-4022 on Leydig Cell Function in Adult Male Rats Biol Reprod, December 1, 2007; 77(6): 1017 - 1026. [Abstract] [Full Text] [PDF]

				N. Renlund, F. H O'Neill, L. Zhang, Y. Sidis, and J. Teixeira Activin receptor-like kinase-2 inhibits activin signaling by blocking the binding of activin to its type II receptor J. Endocrinol., October 1, 2007; 195(1): 95 - 103. [Abstract] [Full Text] [PDF]

				H. Johnston, P. J King, and P. J O'Shaughnessy Effects of ACTH and expression of the melanocortin-2 receptor in the neonatal mouse testis Reproduction, June 1, 2007; 133(6): 1181 - 1187. [Abstract] [Full Text] [PDF]

				P. Kempna, G. Hofer, P. E. Mullis, and C. E. Fluck Pioglitazone Inhibits Androgen Production in NCI-H295R Cells by Regulating Gene Expression of CYP17 and HSD3B2 Mol. Pharmacol., March 1, 2007; 71(3): 787 - 798. [Abstract] [Full Text] [PDF]

				X. Wu, R. Arumugam, S. P. Baker, and M. M. Lee Pubertal and Adult Leydig Cell Function in Mullerian Inhibiting Substance-Deficient Mice Endocrinology, February 1, 2005; 146(2): 589 - 595. [Abstract] [Full Text] [PDF]

				S. Jonard and D. Dewailly The follicular excess in polycystic ovaries, due to intra-ovarian hyperandrogenism, may be the main culprit for the follicular arrest Hum. Reprod. Update, March 1, 2004; 10(2): 107 - 117. [Abstract] [Full Text] [PDF]

				C. P. Houk, E. J. Pearson, N. Martinelle, P. K. Donahoe, and J. Teixeira Feedback Inhibition of Steroidogenic Acute Regulatory Protein Expression in Vitro and in Vivo by Androgens Endocrinology, March 1, 2004; 145(3): 1269 - 1275. [Abstract] [Full Text] [PDF]

				G. Y. Bedecarrats, F. H. O'Neill, E. R. Norwitz, U. B. Kaiser, and J. Teixeira Regulation of gonadotropin gene expression by Mullerian inhibiting substance PNAS, August 5, 2003; 100(16): 9348 - 9353. [Abstract] [Full Text] [PDF]