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* Reproductive Endocrine Unit and
Endocrine Unit, Massachusetts General Hospital, Boston, Massachussetts 02114
It has been 70 years since the name inhibin was used to describe a gonadal factor that negatively regulated pituitary hormone secretion. The majority of this period was required to achieve purification and definitive characterization of inhibin, an event closely followed by identification and characterization of activin and follistatin (FS). In contrast, the last 15–20 years saw a virtual explosion of information regarding the biochemistry, physiology, and biosynthesis of these proteins, as well as identification of activin receptors, and a unique mechanism for FS action—the nearly irreversible binding and neutralization of activin. Many of these discoveries have been previously summarized; therefore, this review will cover the period from the mid 1990s to present, with particular emphasis on emerging themes and recent advances. As the field has matured, recent efforts have focused more on human studies, so the endocrinology of inhibin, activin, and FS in the human is summarized first. Another area receiving significant recent attention is local actions of activin and its regulation by both FS and inhibin. Because activin and FS are produced in many tissues, we chose to focus on a few particular examples with the most extensive experimental support, the pituitary and the developing follicle, although nonreproductive actions of activin and FS are also discussed. At the cellular level, it now seems that activin acts largely as an autocrine and/or paracrine growth factor, similar to other members of the transforming growh factor ß superfamily. As we discuss in the next section, its actions are regulated extracellularly by both inhibin and FS. In the final section, intracellular mediators and modulators of activin signaling are reviewed in detail. Many of these are shared with other transforming growh factor ß superfamily members as well as unrelated molecules, and in a number of cases, their physiological relevance to activin signal propagation remains to be elucidated. Nevertheless, taken together, recent findings suggest that it may be more appropriate to consider a new paradigm for inhibin, activin, and FS in which activin signaling is regulated extracellularly by both inhibin and FS whereas a number of intracellular proteins act to modulate cellular responses to these activin signals. It is therefore the balance between activin and all of its modulators, rather than the actions of any one component, that determines the final biological outcome. As technology and model systems become more sophisticated in the next few years, it should become possible to test this concept directly to more clearly define the role of activin, inhibin, and FS in reproductive physiology.
Key Words: activin • inhibin • follistatin • follistatin-related protein • FSRP/FLRG • transforming growth factor ß • SMADs • activin receptors • signaling • endocrinology • paracrine actions • autocrine actions
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B. D. Cherrington, T. A. Farmerie, C. A. Lents, J. D. Cantlon, M. S. Roberson, and C. M. Clay Activin Responsiveness of the Murine Gonadotropin-Releasing Hormone Receptor Gene Is Mediated by a Composite Enhancer Containing Spatially Distinct Regulatory Elements Mol. Endocrinol., April 1, 2005; 19(4): 898 - 912. [Abstract] [Full Text] [PDF]
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J.L. Juengel and K.P. McNatty The role of proteins of the transforming growth factor-{beta} superfamily in the intraovarian regulation of follicular development Hum. Reprod. Update, March 1, 2005; 11(2): 144 - 161. [Abstract] [Full Text] [PDF]
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S. J. Gregory, C. T. Lacza, A. A. Detz, S. Xu, L. A. Petrillo, and U. B. Kaiser Synergy between Activin A and Gonadotropin-Releasing Hormone in Transcriptional Activation of the Rat Follicle-Stimulating Hormone-{beta} Gene Mol. Endocrinol., January 1, 2005; 19(1): 237 - 254. [Abstract] [Full Text] [PDF]
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Y. Sidis, A. L. Schneyer, and H. T. Keutmann Heparin and Activin-Binding Determinants in Follistatin and FSTL3 Endocrinology, January 1, 2005; 146(1): 130 - 136. [Abstract] [Full Text] [PDF]
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E. del Re, Y. Sidis, D. A. Fabrizio, H. Y. Lin, and A. Schneyer Reconstitution and Analysis of Soluble Inhibin and Activin Receptor Complexes in a Cell-free System J. Biol. Chem., December 17, 2004; 279(51): 53126 - 53135. [Abstract] [Full Text] [PDF]
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B. E. West, G. E. Parker, J. J. Savage, P. Kiratipranon, K. S. Toomey, L. R. Beach, S. C. Colvin, K. W. Sloop, and S. J. Rhodes Regulation of the Follicle-Stimulating Hormone {beta} Gene by the LHX3 LIM-Homeodomain Transcription Factor Endocrinology, November 1, 2004; 145(11): 4866 - 4879. [Abstract] [Full Text] [PDF]
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A. Utomo, X. Jiang, S. Furuta, J. Yun, D. S. Levin, Y.-C. J. Wang, K. V. Desai, J. E. Green, P.-L. Chen, and W.-H. Lee Identification of a Novel Putative Non-selenocysteine Containing Phospholipid Hydroperoxide Glutathione Peroxidase (NPGPx) Essential for Alleviating Oxidative Stress Generated from Polyunsaturated Fatty Acids in Breast Cancer Cells J. Biol. Chem., October 15, 2004; 279(42): 43522 - 43529. [Abstract] [Full Text] [PDF]
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A. L. Schneyer, Q. Wang, Y. Sidis, and P. M. Sluss Differential Distribution of Follistatin Isoforms: Application of a New FS315-Specific Immunoassay J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 5067 - 5075. [Abstract] [Full Text] [PDF]
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D. Tomic, K. P. Miller, H. A. Kenny, T. K. Woodruff, P. Hoyer, and J. A. Flaws Ovarian Follicle Development Requires Smad3 Mol. Endocrinol., September 1, 2004; 18(9): 2224 - 2240. [Abstract] [Full Text] [PDF]
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 C. M. Foster, P. R. Olton, M. S. Racine, D. J. Phillips, and V. Padmanabhan Sex differences in FSH-regulatory peptides in pubertal age boys and girls and effects of sex steroid treatment Hum. Reprod., July 1, 2004; 19(7): 1668 - 1676. [Abstract] [Full Text] [PDF]
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W. Wada, H. Kuwano, Y. Hasegawa, and I. Kojima The Dependence of Transforming Growth Factor-{beta}-Induced Collagen Production on Autocrine Factor Activin A in Hepatic Stellate Cells Endocrinology, June 1, 2004; 145(6): 2753 - 2759. [Abstract] [Full Text] [PDF]
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C. J. Jorgez, M. Klysik, S. P. Jamin, R. R. Behringer, and M. M. Matzuk Granulosa Cell-Specific Inactivation of Follistatin Causes Female Fertility Defects Mol. Endocrinol., April 1, 2004; 18(4): 953 - 967. [Abstract] [Full Text] [PDF]
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Y. Xia, Y. Sidis, and A. Schneyer Overexpression of Follistatin-Like 3 in Gonads Causes Defects in Gonadal Development and Function in Transgenic Mice Mol. Endocrinol., April 1, 2004; 18(4): 979 - 994. [Abstract] [Full Text] [PDF]
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H. T. Keutmann, A. L. Schneyer, and Y. Sidis The Role of Follistatin Domains in Follistatin Biological Action Mol. Endocrinol., January 1, 2004; 18(1): 228 - 240. [Abstract] [Full Text] [PDF]
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S. P. Brothers, J. A. Janovick, and P. M. Conn Unexpected Effects of Epitope and Chimeric Tags on Gonadotropin-Releasing Hormone Receptors: Implications for Understanding the Molecular Etiology of Hypogonadotropic Hypogonadism J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 6107 - 6112. [Abstract] [Full Text] [PDF]
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K. Hayashi, K. D. Carpenter, C. A. Gray, and T. E. Spencer The Activin-Follistatin System in the Neonatal Ovine Uterus Biol Reprod, September 1, 2003; 69(3): 843 - 850. [Abstract] [Full Text] [PDF]
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K. D. Carpenter, K. Hayashi, and T. E. Spencer Ovarian Regulation of Endometrial Gland Morphogenesis and Activin-Follistatin System in the Neonatal Ovine Uterus Biol Reprod, September 1, 2003; 69(3): 851 - 860. [Abstract] [Full Text] [PDF]
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 J. E. Buster Activins, Inhibins, and Follistatins in Reproduction Reproductive Sciences, May 1, 2003; 10(4): 177 - 177. [PDF]
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A. Schneyer, A. Schoen, A. Quigg, and Y. Sidis Differential Binding and Neutralization of Activins A and B by Follistatin and Follistatin Like-3 (FSTL-3/FSRP/FLRG) Endocrinology, May 1, 2003; 144(5): 1671 - 1674. [Abstract] [Full Text] [PDF]
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G. Y. Bedecarrats and U. B. Kaiser Differential Regulation of Gonadotropin Subunit Gene Promoter Activity by Pulsatile Gonadotropin-Releasing Hormone (GnRH) in Perifused L{beta}T2 Cells: Role of GnRH Receptor Concentration Endocrinology, May 1, 2003; 144(5): 1802 - 1811. [Abstract] [Full Text] [PDF]
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A. Krishnan, C. Murdock, J. Allard, M. Cisar, E. Reid, L. Nieman, and J. Segars Pseudo-isolated FSH deficiency caused by an inhibin B-secreting granulosa cell tumour: Case report Hum. Reprod., March 1, 2003; 18(3): 502 - 505. [Abstract] [Full Text] [PDF]
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