科研之友
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摘要
The uterine epithelium of mice and humans undergoes cyclical waves of cell proliferation and differentiation under the regulation of estradiol-17 beta (E-2) and progesterone (P-4). These epithelial cells respond to E-2 with increased protein and DNA synthesis, whereas P-4 inhibits only the E-2-induced DNA synthetic response. Here we show that E-2 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 P-4. 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. E-2 also stimulates an IGF1 receptor (IGF1R) to PI3 kinase to AKT to GSK-3 beta pathway required for activation of the canonical cell cycle machinery that is inhibited by P-4. 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 P-4. Inhibition of mTOR by rapamycin in vivo resulted in inhibition of E-2-induced protein and DNA synthesis. Proliferative diseases of the endometrium such as endometriosis and cancer are common and E-2 dependent. Thus, defining this mTOR pathway suggests that local (intrauterine or peritoneal) rapamycin administration might be a therapeutic option for these diseases.
- 出版日期2015-3-17
