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Regulation and Actions of Smad7 in the Modulation of Activin, Inhibin, and Transforming Growth Factor- Signaling in Anterior Pituitary Cells¹

Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California 92037

Address all correspondence and requests for reprints to: Louise M. Bilezikjian, Ph.D., Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037. E-mail: bilezikjian{at}salk.edu

Activins and transforming growth factor- (TGF) are crucial autocrine, paracrine, and endocrine modulators of anterior pituitary function. Activins regulate most pituitary cells and lactotropes are targets of TGF. Smad2 and Smad3 are two cellular mediators of activin/TGF signaling, whereas Smad7 is as an inducible, negative modulator of the pathway. This study was undertaken to evaluate Smad7 regulation in the pituitary. Activin A rapidly and transiently increased Smad7 messenger RNA (mRNA) levels of rat anterior pituitary (RAP), clonal gonadotrope (T3–1 and LT2), and corticotrope (AtT20) cells with an EC₅₀ of 0.1–0.2 nM. In RAP cells, activin A or TGF1 had equivalent effects that were additive. Follistatin, known to bind and inactivate activins, prevented Smad7 induction by activin. Inhibin A partially antagonized activin A, perhaps reflecting gonadotrope-selective actions. This antagonism was also evident with T3–1 and LT2 gonadotropes. Forskolin had no measurable effect in RAP cells, but increased Smad7 mRNA levels in T3–1 cells and decreased them in LT2 cells. Transient transfection of Smad7 along with 3TPLux, an activin/TGF-responsive reporter, blocked activin-mediated promoter activation in T3–1 and AtT20 cells. In T3–1 cells, which express endogenous follistatin mRNA, a follistatin-luciferase reporter, rFS(rin3)-Luc, was transcriptionally activated by activin A, or when cotransfected with a constitutively active ActRIB [Alk4(T>D)], Smad2, or Smad3. Smad7 blocked rFS(rin3)-Luc activation by activin A or Alk4(T>D). Together, these results point to a role of Smad7 in modulating activin/TGF signaling in the pituitary.

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