title: Stimulatory effect of insulin on theca-interstitial cell proliferation and cell cycle regulatory proteins through MTORC1 dependent pathway.
abstract: The present study examined the effect of insulin-mediated activation of the mammalian target of rapamycin complex 1 (MTORC1) signaling network on the proliferation of primary culture of theca-interstitial (T-I) cells. Our results show that insulin treatment increased proliferation of the T-I cells through the MTORC1-dependent signaling pathway by increasing cell cycle regulatory proteins. Inhibition of ERK1/2 signaling caused partial reduction of insulin-induced phosphorylation of RPS6KB1 and RPS6 whereas inhibition of PI3-kinase signaling completely blocked the insulin response. Pharmacological inhibition of MTORC1 with rapamycin abrogated the insulin-induced phosphorylation of EIF4EBP1, RPS6KB1 and its downstream effector, RPS6. These results were further confirmed by demonstrating that knockdown of Mtor using siRNA reduced the insulin-stimulated MTORC1 signaling. Furthermore, insulin-stimulated T-I cell proliferation and the expression of cell cycle regulatory proteins CDK4, CCND3 and PCNA were also blocked by rapamycin. Taken together, the present studies show that insulin stimulates cell proliferation and cell cycle regulatory proteins in T-I cells via activation of the MTORC1 signaling pathway.
authors.affiliation: Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, MI 48109, United States.
authors.forename: Murugesan
authors.initials: M
authors.lastname: Palaniappan
authors.forename: Bindu
authors.initials: B
authors.lastname: Menon
authors.forename: K M J
authors.initials: KM
authors.lastname: Menon
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002417:Cattle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D007328:Insulin / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D038601:Ribosomal Protein S6 / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013799:Theca Cells / Q000166:cytology*; D013997:Time Factors
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D020929:Mitogen-Activated Protein Kinase Kinases; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D038601:Ribosomal Protein S6; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C499526:Eif4ebp1 protein, rat; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1