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An IGF1/insulin receptor substrate-1 pathway stimulates a mitotic kinase (cdk1) in the uterine epithelium during the proliferative response to estradiol.

ABSTRACT: 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.

SUBMITTER: Walker MP

PROVIDER: S-EPMC4766979 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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An IGF1/insulin receptor substrate-1 pathway stimulates a mitotic kinase (cdk1) in the uterine epithelium during the proliferative response to estradiol.

Walker Michael P MP Diaugustine Richard P RP Zeringue Ernest E Bunger Maureen K MK Schmitt Martina M Archer Trevor K TK Richards R Gregg RG

The Journal of endocrinology 20100826 2

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. Thi ...[more]

PMID: 20798132

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Project description:Glycogen content in mink uterine glandular and luminal epithelia (GE and LE) is maximal during estrus and is depleted before implantation while embryos are in diapause. Uterine glycogen synthesis in vivo is stimulated by estradiol (E2) while its mobilization is induced by progesterone (P4). Nevertheless, treatment of an immortalized mink uterine epithelial cell line (GMMe) with E2 did not affect glycogen production. Interestingly, insulin alone significantly increased synthesis of the nutrient and glycogen content in response to insulin + E2 was greater than for insulin alone. Our objectives were to determine: 1) If insulin receptor protein (INSR) is expressed by mink uterine GE and LE in vivo and if the amount differs between estrus, diapause and pregnancy; 2) if E2, P4 or insulin regulate insulin receptor gene (Insr) expression by GMMe cells, and 3) if E2 and P4 act independently to regulate glycogen metabolism by GMMe cells and/or if their effects are mediated in part through the actions of insulin. The mean (±S.E.) percent INSR content of uterine epithelia was greatest during diapause (GE: 15.65 ± 0.06, LE:16.56 ± 1.25), much less during pregnancy (GE: 2.53 ± 0.60, LE:2.25 ± 0.32) and barely detectable in estrus (GE: 0.03 ± 0.01, LE:0.02 ± 0.01). Glycogen concentrations in GMMe cells increased 10-fold in response to insulin and 20-fold with insulin + E2 when compared to controls. Expression of Insr was increased 2-fold by insulin and insulin + E2 when compared to controls and there was no difference between the two hormone treatments, indicating that E2 does not increase Insr expression in insulin-treated cells. To simulate E2-priming, cells were treated with Insulin + E2 for 24 h, followed by the same hormones + P4 for the second 24 h (Insulin + E2 ? P4) which resulted in Insr and glycogen levels not different from controls. Similarly, cells treated with Insulin + P4 resulted in glycogen concentrations not different from controls. We conclude that the glycogenic actions of E2 on GMMe cells are due to increased responsiveness of the cells to insulin, but not as a result of up-regulation of the insulin receptor. Glycogen mobilization in response to P4 was the result of decreased glycogenesis and increased glycogenolysis occurring concomitantly with reduced Insr expression. Mink uterine glycogen metabolism appears to be regulated in a reproductive cycle-dependent manner in part as a result of the actions of E2 and P4 on cellular responsiveness to insulin.

Dataset Information

An IGF1/insulin receptor substrate-1 pathway stimulates a mitotic kinase (cdk1) in the uterine epithelium during the proliferative response to estradiol.

Publications

An IGF1/insulin receptor substrate-1 pathway stimulates a mitotic kinase (cdk1) in the uterine epithelium during the proliferative response to estradiol.

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