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Department of Neurobiology and Physiology (M.I.S., D.J.L., T.K.W.), Northwestern University, Evanston, Illinois 60208; Department of Medicine (T.K.W.), Northwestern Medical School, Chicago, Illinois 60611; and Department of Human Genetics (H.S., S.A.C.), University of Michigan, Ann Arbor, Michigan 48109
Address all correspondence and requests for reprints to: Teresa K. Woodruff, Ph.D., Department of Neurobiology and Physiology, Northwestern University, 2205 Tech Drive, Evanston, Illinois 60208. E-mail: tkw{at}northwestern.edu.
FSH is controlled by a variety of positive and negative stimuli, and the unique FSHß-subunit is a major target for this regulation. Activin is a key modulator of FSHß transcription and hormone secretion. The signal transduction pathway leading to FSH expression was previously unknown. Here, we show that the transcription factors Smad3 and Smad4 mediate activin-stimulated activity of the rat FSHß promoter in a pituitary-derived cell line, LßT2. Cells were transiently transfected with the rat FSHß promoter fused to a luciferase reporter gene (-338rFSHß-Luc), and a minimal activin-responsive region was identified. Transfection of Smad3, but not the highly related Smad2, led to a ligand-independent stimulation of the FSHß promoter activity. As expected, activin caused an additional increase of luciferase expression, which was blocked by cotreatment with follistatin. Although Smad4 alone had no effect on FSHß transcription, it significantly augmented Smad3 and activin-mediated stimulation of the promoter. A palindromic consensus Smad-binding element in the proximal promoter was found to bind Smad4, and elimination of the region resulted in a loss of activin-mediated FSHß transcription.
The activin signaling pathway is conserved in a number of cells, but FSHß expression is restricted to gonadotropes. A pituitary-specific transcription factor necessary for activin-dependent induction of the FSHß promoter has been identified that permits FSHß expression in nongonadotrope cells. Pitx2 is a member of Pitx subfamily of bicoid-related homeodomain factors that is required for pituitary development and is present in the adult pituitary. This factor was transfected into LßT2 cells, where it caused up-regulation of basal and activin-mediated FSHß promoter activity. Furthermore, cotransfection of Pitx2c with Smad3 in kidney-derived TSA cells resulted in activin-regulated FSHß response, suggesting its important role in tissue-restricted regulation of FSHß by activin. A Pitx2c binding site was identified within the proximal promoter, and elimination of this region also resulted in a loss of activin-regulated FSHß promoter activity. Taken together, these studies suggest that the regulation of FSHß is dependent on activin-mediated signaling factors in concert with pituitary-derived nuclear regulatory proteins.
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