NCBI Summary:
This gene encodes a member of the transducers of regulated cAMP response element-binding protein activity family of transcription coactivators. These proteins promote the transcription of genes targeted by the cAMP response element-binding protein, and therefore play an important role in many cellular processes. Under basal conditions the encoded protein is phosphorylated by AMP-activated protein kinase or the salt-inducible kinases and is sequestered in the cytoplasm. Upon activation by elevated cAMP or calcium, the encoded protein translocates to the nucleus and increases target gene expression. Single nucleotide polymorphisms in this gene may increase the risk of type 2 diabetes. A pseudogene of this gene is located on the long arm of chromosome 5. [provided by RefSeq, Dec 2010]
General function
Nucleic acid binding, DNA binding, Transcription factor
Comment
Cellular localization
Nuclear
Comment
Ovarian function
Steroid metabolism
Comment
Calcineurin and CRTC2 mediate FSH and TGF1 upregulation of Cyp19a1 and Nr5a in ovary granulosa cell. Lai WA 2014 et al.
Estrogens are essential for female reproduction and overall well-being, and estrogens in circulation are largely synthesized in ovarian granulosa cells. Using primary culture of ovarian granulosa cells from gonadotropin-primed immature rats, we recently uncovered that pituitary FSH and ovarian cytokine TGF1 induce calcineurin-mediated dephosphorylation-activation of CREB-regulated transcription coactivator (CRTC2) to modulate the expression of Star, Cyp11a1 and Hsd3b leading to increased progesterone production. This study explored the role of calcineurin and CRTC2 in FSH and TGF1 regulation of Cyp19a1 expression in granulosa cells. Ovarian granulosa cells given FSH had increased aromatase protein at 24 h post-treatment which subsided by 48 h, while TGF1 acting through its type I receptor augmented FSH action with a greater and longer effect. It is known that ovary-specific Cyp19a1 PII-promoter contains crucial response elements for CREB and nuclear receptors LRH-1/NR5A2 and SF-1/NR5A1, and Nr5a2 promoter also has a potential CREB-binding site. Here, we demonstrate FSH plus TGF1 increased LRH-1 and SF-1 protein, and their binding to Cyp19a1 PII-promoter evidenced by chromatin immunoprecipitation analysis. Moreover, pretreatment with calcineurin auto-inhibitory peptide (CNI) abolished the FSH+TGF1- but not FSH-upregulated aromatase activity at 48 h, and the corresponding mRNA changes of Cyp19a1, and Nr5a2 and Nr5a1 at 24 h. Additionally, FSH and TGF1 increased CRTC2 binding to Cyp19a1 PII-promoter and Nr5a2 promoter at 24 h with CREB bound constitutively. In all, this study implicates calcineurin and CRTC2 importantly mediate FSH and TGF1 collateral upregulation of Cyp19a1 expression together with its transcription regulators Nr5a2 and Nr5a1 in ovarian granulosa cells.
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CREB coactivator CRTC2/TORC2 and its regulator calcineurin crucially mediate follicle-stimulating hormone (FSH) and transforming growth factor (TGF?) upregulation of steroidogenesis. Fang WL et al. In vitro and in vivo studies implicate that FSH and TGF? play crucial physiological roles in regulating ovarian granulosa cell function essential to fertility control in females. FSH induces cAMP and calcium signaling, thereby activating transcription factor CREB to upregulate steroidogenic gene expression, and TGF? greatly enhances FSH-stimulated steroidogenesis. A CREB coactivator CRTC2/TORC2 was identified to function as a cAMP and calcium-sensitive coincidence sensor. This led us to explore the role of CRTC2 and its regulator calcineurin in FSH and TGF?-stimulated steroidogenesis. Primary culture of granulosa cells from gonadotropin-primed immature rats was used. Immunoblotting analysis shows that FSH rapidly and transiently induced dephosphorylation/activation of CRTC2, and FSH?+?TGF? additionally induced late-phase CRTC2 dephosphorylation. Immunofluorescence analysis further confirms FSH???TGF? promoted CRTC2 nuclear translocation. Using selective inhibitors, we demonstrate that FSH activated CRTC2 in a PKA- and calcineurin-dependent manner, and TGF? acting through its type I receptor (TGF?I) modulated FSH action in a calcineurin-mediated and PKA-independent fashion. Next, we investigated the involvement of calcineurin and CRTC2 in FSH and TGF?-stimulated steroidogenesis. Calcineurin and TGF?I inhibitor dramatically reduced the FSH???TGF?-increased progesterone synthesis and protein levels of StAR, P450scc and 3?HSD enzyme. Furthermore, chromatin-immunoprecipitation and immunoprecipitation analyses demonstrate that FSH???TGF? differentially increased CRTC2, CREB and CBP binding to these steroidogenic genes, and CREB nuclear association with CRTC2 and CBP. In all, this study reveals for the first time that CRTC2 and calcineurin are critical signaling mediators in FSH and TGF?-stimulated steroidogenesis in ovarian granulosa cells. J. Cell. Physiol. ? 2011 Wiley-Liss, Inc.
Expression regulated by
FSH, Growth Factors/ cytokines
Comment
CRTC2 and Nedd4 ligase involvement in FSH and TGFβ1 upregulation of connexin43 gap junction. Fang WL et al. (2015) The major mission of the ovarian follicle is the timely production of the mature fertilizable oocyte, and this is achieved by gonadotropin-regulated, gap junction-mediated cell-cell communication between the oocyte and surrounding nurturing granulosa cells. We have demonstrated that FSH and transforming growth factor beta 1 (TGFβ1) stimulate Gja1 gene-encoded connexin43 (Cx43) gap junction formation/function in rat ovarian granulosa cells is important for their induction of steroidogenesis; additionally, cAMP-protein kinase A (PKA)- and calcium-calcineurin-sensitive cAMP response element-binding (CREB) coactivator CRTC2 plays a crucial role during steroidogenesis. This study was to explore the potential molecular mechanism whereby FSH and TGFβ1 regulate Cx43 synthesis and degradation, particularly the involvement of CRTC2 and ubiquitin ligase Nedd4. Primary culture of granulosa cells from ovarian antral follicles of gonadotropin-primed immature rats was used. At 48 h post-treatment, FSH plus TGFβ1 increased Cx43 level and gap junction function in a PKA- and calcineurin-dependent manner, and TGFβ1 acting through its type I receptor modulated FSH action. Chromatin-immunoprecipitation analysis reveals FSH induced an early-phase (45 min) and FSH+TGFβ1 further elicited a late-phase (24 h) increase in CRTC2, CREB and CBP binding to the Gja1 promoter. Additionally, FSH+TGFβ1 increased the half-life of hyper-phosphorylated Cx43 (Cx43-P2). Also, the proteasome inhibitor MG132 prevented the brefeldin A (blocker of protein transport through Golgi)-reduced Cx43-P2 level and membrane Cx43 gap junction plaque. This is associated with FSH+TGFβ1-attenuated Cx43 interaction with Nedd4 and Cx43 ubiquitination. In all, this study uncovers that FSH and TGFβ1 upregulation of Cx43 gap junctions in ovarian granulosa cells critically involves enhancing CRTC2/CREB/CBP-mediated Cx43 expression and attenuating ubiquitin ligase Nedd4-mediated proteosomal degradation of Cx43 protein.//////////////////