An IGF1/insulin receptor substrate-1 pathway stimulates a mitotic kinase (cdk1) in the uterine epithelium during the proliferative response to estradiol.
Estrogens are potent mitogens for some target organs, such as the uterus, and cancers that develop in this organ might be linked to the proliferative action of these hormones. However, the mechanism by which estrogens influence the cell cycle machinery is not known. We found that a null mutation for the insulin receptor substrate (IRS)-1, a docking protein that is important for IGF1 signaling, compromised hormone-induced mitosis in the uterine epithelium; BrdU incorporation was not affected. This selective effect on mitosis was associated with a reduction in uterine cyclin B-associated kinase activity; cyclin A-associated kinase activity was not changed. The null mutation also reduced the extent of hormone-induced phosphorylation of endogenous uterine histone H1, as determined with phospho-specific antiserum. Uterine epithelial cyclin dependent kinase (cdk)1 was induced in response to hormone, but the level of the kinase protein, as determined by immunoblotting, was noticeably less in the irs1 null mutant than that in the wild-type (WT) mouse, especially around the time of peak mitosis (24 h). Since IRS-1 binds/activates phosphatidylinositol 3-kinase (PI3K), the absence of this docking protein could impair signaling of a known pathway downstream of AKT that stimulates translation of cell cycle components. Indeed, we found that phosphorylation of uterine AKT (Ser473) in irs1 null mutants was less than that in WTs following treatment. Based on earlier studies, it is also possible that an IGF1/IRS-1/PI3K/AKT pathway regulates posttranslational changes in cdk1. This model may provide insights as to how a growth factor pathway can mediate hormone action on cell proliferation.
Walker
Michael P
MP
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Mail Drop D4-01, PO Box 12233, Research Triangle Park, North Carolina 27709, USA.
Diaugustine
Richard P
RP
Zeringue
Ernest
E
Bunger
Maureen K
MK
Schmitt
Martina
M
Archer
Trevor K
TK
Richards
R Gregg
RG
D000818:Animals; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D014599:Uterus / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology
D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C519530:insulin-like growth factor-1, mouse; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt; D016203:CDC2 Protein Kinase
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