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 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.

Altered gene expression patterns during the initiation and promotion stages of neonatally diethylstilbestrol-induced hyperplasia/dysplasia/neoplasia in the hamster uterus

“…In contrast for PS animals, our WB analyses detected down-regulated IRS-1 expression at the whole organ level (also down-regulated at the mRNA level) that, according to our IHC analyses, involved: 1) lack of signal in the endometrial epithelial compartment of both treatment groups and 2) down-regulated cytoplasm/ECM signal in the stromal/mesenchymal compartment. Further investigations are needed in order to reconcile these observations with the general regulatory and tumor biology considerations listed above and with the complex biochemical pathways with which IRS-1 is implicated in estrogen-induced cell proliferation in the uterus [76]. …”

Role of uterine stromal-epithelial crosstalk in embryo implantation

“…They proposed a mechanism in which IGF1, produced in the stroma, acts via IGF1R in the epithelium to stimulate activation of PI3K/AKT, which in turn phosphorylates and inactivates GSK3β, allowing nuclear accumulation of cyclin D1 and cell cycle progression. Other groups suggested that IGF1 regulates progression through the G2/M rather than G1 phase of the cell cycle (Adesanya et al ., 1999; Walker et al ., 2010). Whatever the actual mechanism, these studies point to a role of IGF1 in executing E-induced epithelial proliferation by acting in a paracrine manner, as shown in Figure 2.…”

Overweight and obesity: a review of their relationship to metabolic syndrome, cardiovascular disease, and cancer in South America

“…The link between IR and cancer may be related to high compensatory levels of insulin. This hormone may increase cell proliferation either directly or by increasing the levels of other more potent growth factors, such as insulin‐like growth factor, which is one of the growth factors responsible for the initial steps of cancer development. However, evidence that IR is the major cause of increased risk of cancer, other than colon cancer, is still inconsistent.…”