title: IGF-I signaling is essential for FSH stimulation of AKT and steroidogenic genes in granulosa cells.
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.
authors: Departments of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors: Ping
authors: P
authors: Zhou
authors: Sarah C
authors: SC
authors: Baumgarten
authors: Yanguang
authors: Y
authors: Wu
authors: Jill
authors: J
authors: Bennett
authors: Nicola
authors: N
authors: Winston
authors: Jennifer
authors: J
authors: Hirshfeld-Cytron
authors: Carlos
authors: C
authors: Stocco
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006107:Granulosa Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D057809:HEK293 Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011962:Receptors, FSH / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity; D013256:Steroids / Q000378:metabolism*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D011962:Receptors, FSH; D013256:Steroids; D007334:Insulin-Like Growth Factor I; D005640:Follicle Stimulating Hormone; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases