No 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 IGF-1 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 phosphospecific antiserum. Uterine epithelial cdk1 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 when compared to that of the wild-type mouse, especially around the time of peak mitosis (24 hours). Since IRS-1 binds/activates PI 3-kinase, 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 irs-1 null mutants was less than that in wild-types following treatment. Based on earlier studies, it is also possible that an IGF-1/IRS-1/PI 3-kinase/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.

Methotrexate is a commonly used therapy for ectopic pregnancies in the outpatient setting. Practitioners should be aware of the potential adverse reactions to methotrexate.

No abstract