期刊
MOLECULAR AND CELLULAR ENDOCRINOLOGY
卷 271, 期 1-2, 页码 45-54出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2007.03.006
关键词
cAMP signaling; follistatin; GnRH; PACAP; gonadotrophs
资金
- NICHD NIH HHS [HD19546] Funding Source: Medline
- PHS HHS [36034] Funding Source: Medline
GnRH applied continuously or in pulses of high frequency increases follistatin, and thereby differentially regulates FSH and LH. This study was conducted in alpha T3-1 and L beta T2 gonadotroph cells to begin to understand the signaling pathways through which GnRH stimulates follistatin synthesis. GnRH increased follistatin expression and stimulated a follistatin-LUC reporter in L beta T2 cells, but was inactive in L beta T2-1 cells. GnRH also increased cAMP levels and stimulated a CAMP-responsive promoter only in L beta T2 cells. Forskolin stimulated follistatin in both cell lines. GnRH activation of follistatin was blocked by the PKA inhibitor H89 and by over-expression of a dominant-negative inhibitor of CREB (A-CREB). Activation was also suppressed by PKC depletion, and was reduced by the PKC inhibitor bisindolylmaleimide. The MEK inhibitor PD98059 blocked activation by GnRH or forskolin implying that MAPK contributes to cAMP/PKA-mediated activation of follistatin. When L beta T2 cells were transfected with follistatin-LUC together with A-CREB, and perifused with GnRH, activation was blocked during continuous GnRH, but stimulation by hourly GnRH pulses was unaffected. These experiments provide evidence that GnRH stimulates follistatin through multiple signaling pathways, and that cAMP-CREB activation is obligatory when GnRH is applied continuously. The finding that follistatin transcription was CREB-dependent with continuous but not pulsatile GnRH implies that the mode of ligand activation of GnRH receptors modifies the transcriptional response by changing the signaling network. These results provide a mechanism linking GnRH pulsatility to the differential control of FSH-beta and LH-beta gene expression through follistatin. (c) 2007 Published by Elsevier Ireland Ltd.
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