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Reproductive Endocrine Unit and National Center for Infertility Research, Massachusetts General Hospital (D.V.T., Y.S., A.S.), Boston, Massachusetts 02144; Microbia, Inc. (D.A.H.), Cambridge, Massachusetts 02139; and Millennium Pharmaceuticals (W.E.H.), Cambridge, Massachusetts 02144
Address all correspondence and requests for reprints to: Dr. Drew V. Tortoriello, Columbia University College of Physicians and Surgeons, Division of Molecular Genetics, Ross Berrie Medical Sciences Pavilion, 1150 St. Nicholas Avenue, New York, New York 10032. E-mail: dvtortoriello{at}pol.net
Follistatin-related protein is a recently discovered glycoprotein that is highly homologous in both primary sequence and exon/intron domain structure to the activin-binding protein, follistatin. We explored their potential for functional redundancy by investigating the relative affinities and kinetics of their interactions with activin, bone morphogenic protein-6, and bone morphogenic protein-7 and by exploring their expression and distribution in human tissues and cells. Follistatin and follistatin-related protein mRNA were ubiquitous by Northern analyses, although their sites of peak distribution differed, with follistatin-related protein and follistatin predominating in the placenta and ovary, respectively. Follistatin-related protein, like follistatin, preferentially bound activin with high affinity and in an essentially irreversible fashion. Although follistatin-related protein, like follistatin, possesses a signal sequence and no known nuclear localization signals, its secretion was undetectable in most cell lines by RIA. Intriguingly, follistatin-related protein was identified as a nuclear protein in human granulosa cells and all human cell lines tested. Furthermore, Western analyses of CHO cells transfected with human follistatin-related protein revealed this protein to reside within the insoluble nuclear protein fraction. We conclude that despite its remarkably high level of similarity to follistatin with regard to structure and activin binding kinetics, follistatin-related protein is a nuclear as well as a secretory protein that may perform distinct intracellular actions.
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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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H.-Q. Wang, K. Takebayashi, K. Tsuchida, M. Nishimura, and Y. Noda Follistatin-Related Gene (FLRG) Expression in Human Endometrium: Sex Steroid Hormones Regulate the Expression of FLRG in Cultured Human Endometrial Stromal Cells J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4432 - 4439. [Abstract] [Full Text] [PDF]
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J. J. Hill, Y. Qiu, R. M. Hewick, and N. M. Wolfman Regulation of Myostatin in Vivo by Growth and Differentiation Factor-Associated Serum Protein-1: A Novel Protein with Protease Inhibitor and Follistatin Domains Mol. Endocrinol., June 1, 2003; 17(6): 1144 - 1154. [Abstract] [Full Text] [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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Y. Sidis, D. V. Tortoriello, W. E. Holmes, Y. Pan, H. T. Keutmann, and A. L. Schneyer Follistatin-Related Protein and Follistatin Differentially Neutralize Endogenous vs. Exogenous Activin Endocrinology, May 1, 2002; 143(5): 1613 - 1624. [Abstract] [Full Text] [PDF]
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