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Submitted on November 23, 2004
Accepted on February 28, 2005
-Subunit Gene
Department of Neurobiology and Physiology, Northwestern University, Evanston, IL; Department of Medicine, Northwestern Medical School, Chicago, IL; Department of Medical and Molecular Genetics and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN
* To whom correspondence should be addressed. E-mail: tkw{at}northwestern.edu.
Synthesis of follicle-stimulating hormone (FSH) by the anterior pituitary is regulated by activin, a member of the transforming growth factor 
(TGF) superfamily of ligands. Activin signals through a pathway that involves the activation of the transcriptional co-regulators Smad2 and Smad3. Previous work from our laboratory demonstrated that Smad3, and not Smad2, is sufficient for stimulation of the rat FSH promoter in a pituitary-derived cell line LT2. Here, we used RNA interference technology to independently decrease the expression of Smad proteins in LT2 cells to further investigate Smad2 and Smad3 roles in activin-dependent regulation of the FSH promoter. Down-regulation of Smad2 protein by small interfering RNA (siRNA) duplexes affects only basal transcription of FSH, while decreased expression of Smad3 abrogates activin-mediated stimulation of FSH transcription.
Although highly related, Smad2 and Smad3 differ in their MH1 domains, where the Smad2 protein contains two additional stretches of amino acids that prevent this factor from binding to DNA. We investigated whether these structural features contribute to differential FSH transactivation by Smad2 and Smad3. A variety of Smad chimera constructs were generated and used in transient transfection studies to address this question. Only co-transfection of chimera constructs that contain the MH1 domain of Smad3 results in activin-mediated stimulation of the rat FSH promoter. Furthermore, the insertion of Smad2 loops into Smad3 protein renders it inactive, suggesting that DNA binding is necessary for Smad3-mediated stimulation of the rat FSH promoter. Taken together, these results indicate that the functional differences between Smad2 and Smad3 in their ability to transactivate the rat FSH promoter lie primarily within the MH1 domain and involve structural motifs that affect DNA binding.
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FSH •
Smad •
Pituitary •
Signal Transduction
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