title: 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.
authors: Technion—Israel Institute of Technology, Haifa, Israel.
authors: Lilach
authors: L
authors: Pnueli
authors: Min
authors: M
authors: Luo
authors: Sihui
authors: S
authors: Wang
authors: Zvi
authors: Z
authors: Naor
authors: Philippa
authors: P
authors: Melamed
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D037201:Follicle Stimulating Hormone, beta Subunit / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids; D054730:Protein Interaction Domains and Motifs; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C519509:Crtc1 protein, mouse; D037201:Follicle Stimulating Hormone, beta Subunit; D050778:NFATC Transcription Factors; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D014157:Transcription Factors; D007987:Gonadotropin-Releasing Hormone; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D019703:Calcineurin