This Article 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 book 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 Bernard, D. J. Articles by Woodruff, T. K. Search for Related Content PubMed PubMed Citation Articles by Bernard, D. J. Articles by Woodruff, T. K.

Mechanisms of Inhibin Signal Transduction

Department of Neurobiology and Physiology, Northwestern University, 2153 N. Campus Drive, Evanston, Illinois 60208

ABSTRACT

Inhibin was first identified as a gonadal hormone that potently inhibits pituitary follicle-stimulating hormone (FSH) synthesis and secretion. Although the notion of a nonsteroidal, gonadally derived inhibitory substance was realized in the early 1930s (McCullagh, 1932), identification of the hormone was not accomplished until more than 50 years later. At that time, inhibin was purified from bovine and porcine follicular fluid and was shown to be produced in two forms through dimeric assembly of an subunit (18 kDa) and one of two closely related ß subunits (ßA and ßB, approximately 14 kDa) (Ling et al., 1985; Miyamoto et al., 1985; Rivier et al., 1985; Robertson et al. Dimers of and ßA and and ßB subunits form inhibin A and inhibin B, respectively. In the process of purifying inhibin, two groups also identified homo- and heterodimers of the inhibin ß subunits (Ling et al., 1986; Vale et al., 1986). These hormones, the activins, were shown to potently stimulate FSH secretion from primary pituitary cultures and are now known to play important roles in growth and development (Woodruff, 1998; Pangas and Woodruff, 2000). Inhibins and activins are considered members of the transforming growth factor-beta (TGF-ß) superfamily of growth and differentiation factors, based on a pattern of conserved cysteine residues in the and ß subunits, similar to other ligands in the family.

Identification of the subunit proteins led to the cloning of their cDNAs and subsequently to their chromosomal mapping in several species (Mason et al., 1985, 1986; Forage et al., 1986; Mayo et al., 1986; Esch et al., 1987; Woodruff et al., 1987; Barton et al., 1989; Hiendleder et al., 200 additional activin-related ß subunits (ßC and ßE in mammals and ßD in Xenopus laevis) also have been identified but do not appear to play a role in FSH regulation (Hotten et al., 1995; Oda et al., 1995; Fang et al., 1996,1997; Loveland et al., 1996; Schmitt et al., 1996>O'Bryan et al., et al., 2000). To date, only one subunit has been reported. The inhibin subunits are expressed in various tissues (Meunier et al., 1988a,1988b) but the gonads are clearly the primary source of circulating inhibins (Woodruff et al., 1996). While inhibins act in a paracrine role in some tissues (Hsueh et al., 1987), their best-understood roles are as endocrine regulators of pituitary FSH. Activins also were purified from follicular fluid but because circulating activin levels generally are low, most actions of the hormones are likely to be paracrine in nature (Woodruff, 1998). Several reviews in the past decade have clearly and thoroughly addressed the characterization and regulation of the inhibins and activins and their roles in reproductive function (Vale et al., 1988; Ying, 1988; Woodruff and Mayo, 1990; Mayo, 1994; Woodruff and Mather, 1995).

In this chapter, we focus our attention on more-recent developments in inhibin research. First, we discuss differential regulation of inhibin isoforms. Specifically, we describe patterns of inhibin A and B secretion in the context of the female reproductive cycle. Second, we review molecular mechanisms of inhibin subunit regulation. Third, while inhibins are best known for their role in pituitary FSH regulation, other functions of the ligands are becoming better understood. We review the animal and human literature addressing the possible role of inhibins in gonadal cancers. While we know "what" inhibins do in various contexts, we have a very limited understanding of "how" the ligands have their effects on target cells. Recently, candidate inhibin receptor molecules have been identified (Draper et al., 1998; Hertan et al., 1999; Lewis et al., 2000; Chung et al., 2000). Next, we detail our current understanding of inhibin signal transduction. Finally, in light of the data reviewed here, we pose questions and outline future directions for inhibin research. While this review is concerned primarily with expression and function of inhibin, activin function and mechanisms of action are described where necessary to shed light on inhibin function. Several reviews of activin's role in reproductive and other processes can be found elsewhere (Woodruff, 1998; Pangas and Woodruff, 2000).

This article has been cited by other articles:

				M. A. Rosencrantz, D. S. Wachs, M. S. Coffler, P. J. Malcom, M. Donohue, and R. J. Chang Comparison of inhibin B and estradiol responses to intravenous FSH in women with polycystic ovary syndrome and normal women Hum. Reprod., October 22, 2009; (2009) dep373v1. [Abstract] [Full Text] [PDF]

				P. Lamba, J. Fortin, S. Tran, Y. Wang, and D. J. Bernard A Novel Role for the Forkhead Transcription Factor FOXL2 in Activin A-Regulated Follicle-Stimulating Hormone {beta} Subunit Transcription Mol. Endocrinol., July 1, 2009; 23(7): 1001 - 1013. [Abstract] [Full Text] [PDF]

				C. Glidewell-Kenney, J. Weiss, L. A. Hurley, J. E. Levine, and J. L. Jameson Estrogen Receptor {alpha} Signaling Pathways Differentially Regulate Gonadotropin Subunit Gene Expression and Serum Follicle-Stimulating Hormone in the Female Mouse Endocrinology, August 1, 2008; 149(8): 4168 - 4176. [Abstract] [Full Text] [PDF]

				E.E. At-Taras, A.J. Conley, T. Berger, and J.F. Roser Reducing Estrogen Synthesis Does Not Affect Gonadotropin Secretion in the Developing Boar Biol Reprod, January 1, 2006; 74(1): 58 - 66. [Abstract] [Full Text] [PDF]

				S. A. Sweeney and P. A. Johnson Messenger RNA and Protein Expression Analysis of Betaglycan in the Pituitary and Ovary of the Domestic Hen Biol Reprod, January 1, 2005; 72(1): 172 - 178. [Abstract] [Full Text] [PDF]

				J. C. Corton, U. Apte, S. P. Anderson, P. Limaye, L. Yoon, J. Latendresse, C. Dunn, J. I. Everitt, K. A. Voss, C. Swanson, et al. Mimetics of Caloric Restriction Include Agonists of Lipid-activated Nuclear Receptors J. Biol. Chem., October 29, 2004; 279(44): 46204 - 46212. [Abstract] [Full Text] [PDF]

				M. Hermansson, Y. Sawaji, M. Bolton, S. Alexander, A. Wallace, S. Begum, R. Wait, and J. Saklatvala Proteomic Analysis of Articular Cartilage Shows Increased Type II Collagen Synthesis in Osteoarthritis and Expression of Inhibin {beta}A (Activin A), a Regulatory Molecule for Chondrocytes J. Biol. Chem., October 15, 2004; 279(42): 43514 - 43521. [Abstract] [Full Text] [PDF]

				A. S. Dighe, F. J. Hayes, J. Khosravi, U. Bodani, and P. M. Sluss Comparison of Inhibin A Immunoassays: Recommendation for Adoption of Standardized Reporting Clin. Chem., April 1, 2004; 50(4): 767 - 769. [Full Text] [PDF]

				D. J. Bernard, K. H. Burns, B. Haupt, M. M. Matzuk, and T. K. Woodruff Normal Reproductive Function in InhBP/p120-Deficient Mice Mol. Cell. Biol., July 15, 2003; 23(14): 4882 - 4891. [Abstract] [Full Text] [PDF]

				F. Jimenez-Krassel, M. E. Winn, D. Burns, J. L. H. Ireland, and J. J. Ireland Evidence for a Negative Intrafollicular Role for Inhibin in Regulation of Estradiol Production by Granulosa Cells Endocrinology, May 1, 2003; 144(5): 1876 - 1886. [Abstract] [Full Text] [PDF]

				S. Hasthorpe Clonogenic Culture of Normal Spermatogonia: In Vitro Regulation of Postnatal Germ Cell Proliferation Biol Reprod, April 1, 2003; 68(4): 1354 - 1360. [Abstract] [Full Text] [PDF]

				J. C. Fleet, L. Wang, O. Vitek, B. A. Craig, and H. J. Edenberg Gene expression profiling of Caco-2 BBe cells suggests a role for specific signaling pathways during intestinal differentiation Physiol Genomics, March 18, 2003; 13(1): 57 - 68. [Abstract] [Full Text] [PDF]

				C. Welt, Y. Sidis, H. Keutmann, and A. Schneyer Activins, Inhibins, and Follistatins: From Endocrinology to Signaling. A Paradigm for the New Millennium Experimental Biology and Medicine, October 1, 2002; 227(9): 724 - 752. [Abstract] [Full Text] [PDF]

				T. M. Plant and G. R. Marshall The Functional Significance of FSH in Spermatogenesis and the Control of Its Secretion in Male Primates Endocr. Rev., December 1, 2001; 22(6): 764 - 786. [Abstract] [Full Text] [PDF]