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Submitted on January 10, 2002
Accepted on August 27, 2002
1 Prince Henry's Institute of Medical Research, Clayton, Australia
* To whom correspondence should be addressed. E-mail: jfethier{at}uottawa.ca.
Activin stimulates expression of GnRH receptor (GnRHR) and FSH (FSH) ß-subunit in gonadotropes. Inhibin antagonises activin actions on the gonadotropes, but its molecular mechanism of action remains poorly understood. It has been suggested that inhibin exerts its antagonistic effects by competing with activin for the binding of the activin receptor complex. Betaglycan has recently been identified as an inhibin-binding accessory protein in this process. Since both inhibin and TGFß bind betaglycan, we examined whether TGFß can modify inhibin's antagonism of activin-induced transcription in gonadotrope cells. Two activin-responsive reporter constructs were used, the first containing 5.5 kb of the ovine FSHß promoter (oFSHßluc), and the second containing three copies of the activin-responsive sequence of the GnRHR promoter (3XGRAS-PRL-lux). These constructs were transfected into the gonadotrope cell line LßT2. The oFSHßluc and 3XGRAS-PRL-lux activities stimulated by 0.5 nM activin-A were decreased by up to 50% in a dose-dependent manner by inhibin-A. TGFß1 and TGFß2 (0 - 4 nM) alone or in the presence of activin-A did not significantly affect the promoter elements. However, with increasing doses of TGFß1 or TGFß2, inhibin-A antagonism of activin-A activity was partly or completely reversed. Competition studies with radiolabeled inhibin-A showed that TGFß1 and TGFß2 competed with [125I]inhibin for the binding to LßT2 cells (IC50 = 280 and 72 pM, respectively). Immunoprecipitation studies of [125I]inhibin-A cross-linked receptor complexes confirmed that TGFß1 and TGFß2 competed with inhibin-A for the binding of betaglycan. These results suggest that TGFß competition with inhibin for binding to betaglycan interferes with inhibin's suppression of activin-induced FSHß and GnRHR promoters in LßT2 cells. We propose that under certain circumstances, TGFß may facilitate activin biological activity by hindering the access of inhibin to its co-receptor betaglycan.
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