Activation of protein synthesis in mouse uterine epithelial cells by estradiol-17[Beta] is mediated by a PKC-ERK1/2-mTOR signaling pathway

The uterine epithelium of mice and humans undergoes cyclical waves of cell proliferation and differentiation under the regulation of estradiol-17β (...) and progesterone (...). These epithelial cells respond to ... with increased protein and DNA synthesis, whereas ... inhibits only the ...-induced DNA synthetic response. Here we show that ... regulates protein synthesis in these epithelial cells through activating PKC that in turn stimulates ERK1/2 to phosphorylate and thereby activate the central regulator of protein synthesis mechanistic target of rapamycin (mTOR). This mTOR pathway is not inhibited by ... Inhibitor studies with an estrogen receptor (ESR1) antagonist showed the dependence of this mTOR pathway on ESR1 but that once activated, a phosphorylation cascade independent of ESR1 propagates the pathway. ... also stimulates an IGF1 receptor (IGF1R) to PI3 kinase to AKT to GSK-3β pathway required for activation of the canonical cell cycle machinery that is inhibited by ... PKC activation did not stimulate this pathway nor does inhibition of PKC or ERK1/2 affect it. These studies therefore indicate a mechanism whereby DNA and protein synthesis are regulated by two ESR1-activated pathways that run in parallel with only the one responsible for the initiation of DNA synthesis blocked by ... Inhibition of mTOR by rapamycin in vivo resulted in inhibition of ...-induced protein and DNA synthesis. Proliferative diseases of the endometrium such as endometriosis and cancer are common and ... dependent. Thus, defining this mTOR pathway suggests that local (intrauterine or peritoneal) rapamycin administration might be a therapeutic option for these diseases. (ProQuest: ... denotes formulae/symbols omitted.)