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This version published online on December 23, 2002
Molecular Endocrinology, doi:10.1210/me.2002-0081
A more recent version of this article appeared on March 1, 2003
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Submitted on February 22, 2002
Accepted on December 12, 2002

Regulation of the Rat FSH {beta}-Subunit Promoter by Activin

Magdalena I. Suszko1, Denise J. Lo1, Hoonkyo Suh1, Sally A. Camper1, and Teresa K. Woodruff1*

1 Department of Neurobiology and Physiology, Northwestern University, Evanston, IL Department of Medicine, Northwestern Medical School, Chicago, IL Department of Human Genetics, University of Michigan, Ann Arbor, MI

* To whom correspondence should be addressed. E-mail: tkw{at}northwestern.edu.

FSH (FSH) is controlled by a variety of positive and negative stimuli and the unique FSH{beta}-subunit is a major target for this regulation. Activin is a key modulator of FSH{beta} 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 FSH{beta} promoter in a pituitary-derived cell line, L{beta}T2. Cells were transiently transfected with the rat FSH{beta} promoter fused to a luciferase reporter gene (-338rFSH{beta}-Luc) and a minimal activin-responsive region identified. Transfection of Smad3, but not the highly related Smad2, led to a ligand-independent stimulation of the FSH{beta} promoter activity. As expected, activin caused an additional increase of luciferase expression, which was blocked by co-treatment with follistatin. Although Smad4 alone had no effect on FSH{beta} transcription, it significantly augmented Smad3 and activin-mediated stimulation of the promoter. A palindromic consensus Smad-binding element (SBE) in the proximal promoter was found to bind Smad4 and elimination of the region resulted in a loss of activin-mediated FSH{beta} transcription.

The activin signaling pathway is conserved in a number of cells, but FSH{beta} expression is restricted to gonadotropes. A pituitary-specific transcription factor necessary for activin-dependent induction of the FSH{beta} promoter has been identified that permits FSH{beta} expression in non-gonadotrope 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 L{beta}T2 cells where it caused up-regulation of basal and activin-mediated FSH{beta} promoter activity. Further, co-transfection of Pitx2c with Smad3 in kidney-derived TSA cells resulted in activin-regulated FSH{beta} response, suggesting its important role in tissue-restricted regulation of FSH{beta} 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 FSH{beta} promoter activity. Taken together, these studies suggest that the regulation of FSH{beta} is dependent on activin-mediated signaling factors in concert with pituitary-derived nuclear regulatory proteins.
Key words: TGF{beta} • FSH • Smad • Pituitary • Signal Transduction




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