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J. Biol. Chem., Vol. 283, Issue 11, 7016-7026, March 14, 2008

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A Smad-binding Element in Intron 1 Participates in Activin-dependent Regulation of the Follistatin Gene^*

From the Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, California 92037

Follistatins exert critical autocrine or paracrine control in many tissues by binding and bio-neutralizing activin and several other transforming growth factor-β ligands. In the pituitary, activin acts locally to induce follistatin expression and thus modulate its own actions. This local feedback loop safeguards against excessive activin signaling and maintains the necessary balance of activin and follistatin tone. To better understand the mechanisms underlying the activation of follistatin by activin A, follistatin transcription was evaluated in gonadotrope-derived T3-1 cells. Transient transfection experiments established that follistatin-luciferase plasmids that incorporate up to 2.86 kb of the upstream region of the rat follistatin gene are not induced by activin A in T3-1 cells. On the other hand, plasmids that incorporate intron 1 are responsive to activin A and induced by a constitutively active form of ALK4. These experiments ultimately identified a conserved Smad-binding element (SBE1) in intron 1, between +1791 and +1795. In T3-1 cells treated with activin A, SBE1 preferentially recruits Smad3, but not Smad2, and mediates Smad3-dependent activation of follistatin transcription. shRNA knockdown of endogenous Smad3 in these cells compromises SBE1-mediated transcription in response to activin A and interferes with its ability to positively regulate follistatin mRNA levels. The findings of the current work illustrate the critical role of intron 1 of the follistatin gene in mediating Smad-dependent effects of activin and regulating the expression level of this gene in some cell types, such as pituitary cells of gonadotrope lineage.

Received for publication, November 20, 2007 , and in revised form, January 7, 2008.

^* This work was supported in part by National Institutes of Health Grant HD46941 and by the Foundation for Medical Research and National Institutes of Health Grant HD13527 (to J. M. V. and W. W. V.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ A Senior Foundation for Medical Research Investigator.

² To whom correspondence should be addressed: Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-453-4100, ext. 1539; Fax: 858-552-1546; E-mail: bilezikjian{at}salk.edu.

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				B. Bak, L. Carpio, J. L Kipp, P. Lamba, Y. Wang, R.-S. Ge, M. P Hardy, K. E Mayo, and D. J Bernard Activins regulate 17{beta}-hydroxysteroid dehydrogenase type I transcription in murine gonadotrope cells J. Endocrinol., April 1, 2009; 201(1): 89 - 104. [Abstract] [Full Text] [PDF]

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