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Submitted on July 7, 2003
Accepted on December 19, 2003
subunit in mouse gonadotrope cells
1 Center for Biomedical Research, Population Council and The Rockefeller University, 1230 York Ave., New York, NY 10021
* To whom correspondence should be addressed. E-mail: dbernard{at}popcbr.rockefeller.edu.
The activins are pleiotropic members of the transforming growth factor 
(TGF) superfamily. Within the anterior pituitary gland, activins stimulate FSH synthesis in an autocrine/paracrine fashion by stimulating transcription of the FSH subunit gene. Here, the mechanisms mediating this effect were investigated in the murine gonadotrope cell line, LT2. Recombinant activin A and activin B dose- and time-dependently stimulated endogenous FSH mRNA expression. FSH primary transcript and mRNA levels were increased within 30-60 min., but these effects were blocked by pre-incubation with the transcription inhibitor actinomycin-D, suggesting that the FSH gene is a direct target of the activin signal transduction cascade. In other systems, activin signals are transduced through a heteromeric serine/threonine receptor complex, which includes the signaling activin type IB receptor (ALK4). Transfection of a constitutively active form of the receptor, ALK4T206D, stimulated FSH mRNA levels. Over-expression of the inhibitory SMAD7 blocked this effect, as well as activin-stimulated FSH transcription. Because SMAD7 functions by preventing access of SMAD2 and SMAD3 to ALK4, these data suggested that both activins and ALK4 require SMAD2 and/or SMAD3 to affect FSH transcription. Consistent with this idea, activin A stimulated SMAD2 and SMAD3 phosphorylation and nuclear translocation within 5-10 min in LT2 cells. Transient transfection of SMAD3, but not SMADs 1, 2, 4, 5 or 8, stimulated endogenous FSH mRNA levels. The results of SMAD2 transfection studies were inconclusive, however, because of a persistent failure to over-express the full-length SMAD2 protein specifically in LT2 cells. To assess more directly roles for both SMAD2 and SMAD3 in activin-stimulated FSH expression, RNA interference was used to decrease endogenous SMAD protein levels in LT2 cells. Activin A- and ALK4T206D-stimulated transcription of the FSH gene were significantly attenuated by the depletion of either SMAD2 or SMAD3. Collectively, these data suggest that activins use both SMAD2- and SMAD3-dependent mechanisms to stimulate FSH transcription in mouse gonadotrope cells.
superfamily •
signal transduction •
pituitary
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