Mechanism of negative modulation of FSH signaling by salt-inducible kinases in rat granulosa cells.
Mechanism of negative modulation of FSH signaling by salt-inducible kinases in rat granulosa cells.
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DOI：
10.3389/fendo.2022.1026358
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发表时间：
2022
影响因子：
5.2
通讯作者：
Stocco, Carlos
中科院分区：
文献类型：
--
作者：
Armouti, Marah;Rodriguez-Esquivel, Miriam;Stocco, Carlos
排卵前卵泡的最佳发育需要卵泡刺激素（FSH）。最近的研究结果表明，盐诱导激酶（SIKs）抑制FSH在人类和啮齿动物中的作用。本报告旨在增加我们对SIKs参与抑制原代大鼠颗粒细胞（GC）中FSH作用的分子机制的理解。结果表明，FSH引起Sik 1 mRNA的瞬时诱导。与此相反，抑制SIK对FSH受体表达没有影响。接下来，我们确定了抑制SIK是否增强了FSH信号通路的几种连续直接激活剂的作用。研究结果表明，抑制SIK刺激毛喉素，cAMP，蛋白激酶A（PKA）和cAMP反应元件结合蛋白（CREB）的类固醇基因的诱导。值得注意的是，FSH对CREB和AKT磷酸化的刺激并不受SIK抑制的影响。因此，我们分析了假定的CREB辅因子的表达和激活，并证明GC表达CREB调节的转录辅激活因子（CRTC 2），FSH处理和抑制SIK增加了该因子的核表达。我们的结论是，SIKs通过影响位于cAMP/PKA和CREB之间的因子来靶向FSH通路，并提出SIKs控制卵巢GC中CRTC 2的活性。研究结果首次表明，SIKs减弱了GC对FSH，cAMP，PKA和CREB的反应，为SIKs在调节卵巢功能和女性生育力方面的关键作用提供了进一步的证据。
The optimal development of preovulatory follicles needs follicle-stimulating hormone (FSH). Recent findings revealed that salt-inducible kinases (SIKs) inhibit FSH actions in humans and rodents. This report seeks to increase our understanding of the molecular mechanisms controlled by SIKs that participate in the inhibition of FSH actions in primary rat granulosa cells (GCs). The results showed that FSH causes a transient induction of Sik1 mRNA. In contrast, SIK inhibition had no effects on FSH receptor expression. Next, we determined whether SIK inhibition enhances the effect of several sequential direct activators of the FSH signaling pathway. The findings revealed that SIK inhibition stimulates the induction of steroidogenic genes by forskolin, cAMP, protein kinase A (PKA), and cAMP-response element-binding protein (CREB). Strikingly, FSH stimulation of CREB and AKT phosphorylation was not affected by SIK inhibition. Therefore, we analyzed the expression and activation of putative CREB cofactors and demonstrated that GCs express CREB-regulated transcriptional coactivators (CRTC2) and that FSH treatment and SIK inhibition increase the nuclear expression of this factor. We concluded that SIKs target the FSH pathway by affecting factors located between cAMP/PKA and CREB and propose that SIKs control the activity of CRTC2 in ovarian GCs. The findings demonstrate for the first time that SIKs blunt the response of GCs to FSH, cAMP, PKA, and CREB, providing further evidence for a crucial role for SIKs in regulating ovarian function and female fertility.
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DOI：
10.1038/nrm3072
发表时间：
2011-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.4
作者：
Katoh, Yoshiko;Takemori, Hiroshi;Okamoto, Mitsuhiro
通讯作者：
Okamoto, Mitsuhiro
影响因子：
9.2
作者：
Bittinger, MA;McWhinnie, E;Labow, M
通讯作者：
Labow, M
影响因子：
4.8
作者：
Bennett, Jill;Baumgarten, Sarah C.;Stocco, Carlos
通讯作者：
Stocco, Carlos
影响因子：
--
作者：
McCubrey JA;Steelman LS;Bertrand FE;Davis NM;Sokolosky M;Abrams SL;Montalto G;D'Assoro AB;Libra M;Nicoletti F;Maestro R;Basecke J;Rakus D;Gizak A;Demidenko ZN;Cocco L;Martelli AM;Cervello M
通讯作者：
Cervello M