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IGF-I Signaling Is Essential for FSH Stimulation of AKT and Steroidogenic Genes in Granulosa Cells

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Title: IGF-I Signaling Is Essential for FSH Stimulation of AKT and Steroidogenic Genes in Granulosa Cells
Author(s): Zhou, Ping; Baumgarten, Sarah C.; Wu, Yanguang; Bennett, Jill; Winston, Nicola; Hirshfeld-Cytron, Jennifer; Stocco, Carlos
Abstract: FSH and IGF-I synergistically stimulate gonadal steroid production; conversely, silencing the FSH or the IGF-I genes leads to infertility and hypogonadism. To determine the molecular link between these hormones, we examined the signaling cross talk downstream of their receptors. In human and rodent granulosa cells (GCs), IGF-I potentiated the stimulatory effects of FSH and cAMP on the expression of steroidogenic genes. In contrast, inhibition of IGF-I receptor (IGF-IR) activity or expression using pharmacological, genetic, or biochemical approaches prevented the FSH- and cAMP-induced expression of steroidogenic genes and estradiol production. In vivo experiments demonstrated that IGF-IR inactivation reduces the stimulation of steroidogenic genes and follicle growth by gonadotropins. FSH or IGF-I alone stimulated protein kinase B (PKB), which is also known as AKT and in combination synergistically increased AKT phosphorylation. Remarkably, blocking IGF-IR expression or activity decreased AKT basal activity and abolished AKT activation by FSH. In GCs lacking IGF-IR activity, FSH stimulation of Cyp19 expression was rescued by overexpression of constitutively active AKT. Our findings demonstrate, for the first time, that in human, mouse, and rat GCs, the well-known stimulatory effect of FSH on Cyp19 and AKT depends on IGF-I and on the expression and activation of the IGF-IR.
Issue Date: 2013-03
Publisher: Endocrine Society
Citation Info: Zhou P, Baumgarten SC, Wu Y, Bennett J, Winston N, Hirshfeld-Cytron J, Stocco C. IGF-I Signaling Is Essential for FSH Stimulation of AKT and Steroidogenic Genes in Granulosa Cells. Mol Endocrinol. 2013 Jan 22. doi:10.1210/me.2012-1307
Type: Article
Description: This is a copy of an article published in the Molecular Endocrinology © 2013 Endocrine Society. The publication is available at http://mend.endojournals.org/
URI: http://hdl.handle.net/10027/10653
ISSN: 1944-9917
Sponsor: This work was supported by National Institutes of Health Grants R01HD057110 and R21HD066233.
Date Available in INDIGO: 2014-04-15
 

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