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Abstract

Mechanisms of inhibin signal transduction (PDF) (HTML) 
Bernard,Daniel J.; Chapman,Stacey C.; Woodruff,Teresa K.
Recent Progress in Hormone Research 56(1): 417-450
Publication date: 2001

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Inhibin was first identified as a gonadal hormone that potentlyinhibits pituitary follicle-stimulating hormone (FSH) synthesisand secretion. Although the notion of a nonsteroidal, gonadallyderived inhibitory substance was realized in the early 1930s(McCullagh, 1932), identification of the hormone was not accomplisheduntil more than 50 years later. At that time, inhibin was purifiedfrom bovine and porcine follicular fluid and was shown to beproduced 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) (Linget al., 1985; Miyamoto et al., 1985; Rivier et al., 1985; Robertsonet al. Dimers of and ßA and and ßB subunitsform inhibin A and inhibin B, respectively. In the process ofpurifying inhibin, two groups also identified homo- and heterodimersof the inhibin ß subunits (Ling et al., 1986; Valeet al., 1986). These hormones, the activins, were shown to potentlystimulate FSH secretion from primary pituitary cultures andare now known to play important roles in growth and development(Woodruff, 1998; Pangas and Woodruff, 2000). Inhibins and activinsare considered members of the transforming growth factor-beta(TGF-ß) superfamily of growth and differentiationfactors, based on a pattern of conserved cysteine residues inthe and ß subunits, similar to other ligands in thefamily.Identification of the subunit proteins led to the cloning oftheir cDNAs and subsequently to their chromosomal mapping inseveral 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-relatedß subunits (ßC and ßE in mammalsand ßD in Xenopus laevis) also have been identifiedbut do not appear to play a role in FSH regulation (Hotten etal., 1995; Oda et al., 1995; Fang et al., 1996,1997; Lovelandet al., 1996; Schmitt et al., 1996>O'Bryan et al., et al., 2000).To date, only one subunit has been reported. The inhibin subunitsare expressed in various tissues (Meunier et al., 1988a,1988b)but the gonads are clearly the primary source of circulatinginhibins (Woodruff et al., 1996). While inhibins act in a paracrinerole in some tissues (Hsueh et al., 1987), their best-understoodroles are as endocrine regulators of pituitary FSH. Activinsalso were purified from follicular fluid but because circulatingactivin levels generally are low, most actions of the hormonesare likely to be paracrine in nature (Woodruff, 1998). Severalreviews in the past decade have clearly and thoroughly addressedthe characterization and regulation of the inhibins and activinsand their roles in reproductive function (Vale et al., 1988;Ying, 1988; Woodruff and Mayo, 1990; Mayo, 1994; Woodruff andMather, 1995).In this chapter, we focus our attention on more-recent developmentsin inhibin research. First, we discuss differential regulationof inhibin isoforms. Specifically, we describe patterns of inhibinA and B secretion in the context of the female reproductivecycle. Second, we review molecular mechanisms of inhibin subunitregulation. Third, while inhibins are best known for their rolein pituitary FSH regulation, other functions of the ligandsare becoming better understood. We review the animal and humanliterature addressing the possible role of inhibins in gonadalcancers. While we know "what" inhibins do in various contexts,we have a very limited understanding of "how" the ligands havetheir effects on target cells. Recently, candidate inhibin receptormolecules have been identified (Draper et al., 1998; Hertanet 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 questionsand outline future directions for inhibin research. While thisreview is concerned primarily with expression and function ofinhibin, activin function and mechanisms of action are describedwhere necessary to shed light on inhibin function. Several reviewsof activin's role in reproductive and other processes can befound elsewhere (Woodruff, 1998; Pangas and Woodruff, 2000).

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