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Evidence That Pituitary Adenylate Cyclase Activating Polypeptide Suppresses Follicle-Stimulating Hormone-ß Messenger Ribonucleic Acid Levels by Stimulating Follistatin Gene Transcription¹

Department of Medicine (S.J.W., T.T.), University of Pittsburgh, Pittsburgh, Pennsylvania 15213; and Department of Medicine (A.C.D.), University of Virginia, Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Stephen J. Winters, M.D., Department of Medicine, University of Pittsburgh Medical Center, Montefiore N-919, 200 Lothrop Street, Pittsburgh, Pennsylvania 15213. E-mail: winters{at}med1.dept-med.pitt.edu

There is accumulating evidence to suggest that pituitary adenylate cyclase-activating polypeptide (PACAP) may be an important modulator of gonadotrope function. One of the actions of PACAP identified previously is to decrease FSHß messenger RNA (mRNA) levels. In the present series of experiments we demonstrate that PACAP-induced suppression of FSHß mRNA correlates with a rise in follistatin mRNA levels in primary pituitary cell cultures. Transient transfection of gonadotrope-derived T3–1 cells with a rat follistatin promoter-luciferase reporter plasmid reveals that PACAP stimulates follistatin gene transcription. PACAP stimulation of LUC activity was maximal at concentrations as low at 1 nM. Furthermore, in T3–1 cells PACAP activation of the follistatin promoter appears to be via the cAMP- dependent protein kinase A pathway. Accordingly, we propose that PACAP stimulates follistatin transcription, which neutralizes activin activity and thereby reduces FSHß mRNA. Since PACAP and follistatin are colocalized in multiple tissues including the brain, adrenals, and gonads, our findings may reflect a broadly distributed autocrine/paracrine mechanism for modification of activin effects that is under PACAP control.

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