Follicle-stimulating hormone (FSH) is necessary and sufficient to induce maturation of ovarian follicles to a mature, preovulatory phenotype in the intact animal, resulting in the generation of mature eggs and production of estrogen. FSH accomplishes these actions by inducing a complex pattern of gene expression in target granulosa cells that is regulated by input from many different signaling cascades, including those for the extracellular regulated kinases (ERKs), p38 mitogen-activated protein kinases (MAPKs), and phosphatidylinositol-3 kinase (PI3K). The upstream kinase that appears to be responsible for initiating all of the signaling that regulates gene expression in these epithelial cells is protein kinase A (PKA). PKA not only signals to directly phosphorylate transcription factors like cAMP response element binding protein and to promote chromatin remodeling by phosphorylating histone H3, this versatile kinase also enhances the activity of the p38 MAPK, ERK, and PI3K pathways. Additionally, accumulating evidence suggests that activation of a single signaling cascade downstream of PKA is not sufficient to activate target gene expression. Rather, cross-talk between and among signaling cascades is required. We will review the signaling cascades activated by FSH in granulosa cells and how these cascades contribute to the regulation of select target gene expression.
KeywordsFollicle-stimulating hormone; Mitogen-activated protein kinase; Female reproduction; Hypoxiainduced factor 1; Histone H3; Protein kinase A Abbreviations AKAP, A kinase anchoring protein; Aromatase, P450 aromatase; CBP, CREB binding protein; ChIP, chromatin immunoprecipitation assay; CREB, cAMP response element binding protein; EGF, epidermal growth factor; Egr-1, early growth response protein-1; ERK, extracellular regulated kinase; Epac, exchange proteins activated by cAMP; FSH, follicle-stimulating hormone; GIOT-1, gonadotropin-inducible ovarian transcription factor-1; GPCR, G-protein-coupled receptor; HIF-1, hypoxia-induced factor-1; IGF, insulin-like growth factor; LH, luteinizing hormone; LRH-1, liver receptor homolog-1; MAP2D, microtubule-associated protein 2D; MAPK, mitogen-activated protein kinase; MEK, mitogen-and extracellular-regulated kinase kinase; MK, MAPK-activated protein kinases; MNK, MAPK-interacting kinase; mTOR, mammalian target of rapamycin; p70S6K, p70 ribosomal S6 kinase; PDE, phosphodiesterase; PI3K, phosphatidylinositol 3-kinase; PKA, protein kinase A; PKC, protein kinase C; PKI, PKA inhibitor peptide; PTP, protein tyrosine phosphatase; R, PKA regulatory subunits; RSK, p90 ribosomal S6 protein kinase; SCC, P450 cholesterol side chain cleavage; SF-1, steroidogenic factor-1; SGK, serum glucocorticoid kinase; Sp1/Sp3, specific