Calcineurin Mediates the Gonadotropin-Releasing Hormone Effect on Expression of Both Subunits of the Follicle-Stimulating Hormone through Distinct Mechanisms

Abstract

Gonadotropin-releasing hormone (GnRH) regulates the expression of all three gonadotropin genes, encoding the common α subunit (αGSU) and hormone-specific β subunits, through the activation of several signal transduction pathways. We have shown that GnRH also upregulates calcineurin, and we hypothesized that calcineurin mediates the effects of GnRH on the transcription of the αGSU and follicle-stimulating hormone β (FSHβ) genes through two of its targets: nuclear factor of activated T cells (NFAT) and CREB-regulated transcription coactivator (TORC). We show that calcineurin is essential for GnRH-induced expression of both genes but that NFAT and TORC1 play quite distinct roles in activating each gene. GnRH induces calcineurin-dependent nuclear import of NFAT3, which activates the αGSU promoter, while TORC1 also mediates GnRH activation of this promoter, but not through CREB. GnRH initially stimulates the degradation of TORC1 but protects the N terminus of the newly synthesized protein to enhance its activity. Calcineurin induces Nur77 expression, likely via NFAT3, and Nur77 interacts synergistically with TORC1 and CREB to increase FSHβ promoter activity. Although TORC plays a role in the basal activity of the FSHβ promoter, it does not interact with phosphorylated CREB and probably does not play a major role in direct GnRH signaling to this gene. TORC may be part of an alternatively regulated pathway, possibly involving cross talk with other stimulatory hormones.

ACKNOWLEDGMENTS

This research was supported by the Biomedical Research Council, Singapore, and the European Framework program Marie Curie Actions.

We thank Jean-Rene Cardinaux, Yehuda Assraf, Dong-Yan Jin, Hiroshi Takemori, Yoshiaki Tsuji, Mark Featherstone, and Chi-Wing Chow for the various constructs and P. Mellon for the αT3-1 and LβT2 cells.