Activation of protein synthesis in mouse uterine epithelial cells by estradiol-17β 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 (E2) and progesterone (P4). These epithelial cells respond to E2 with increased protein and DNA synthesis, whereas P4 inhibits only the E2-induced DNA synthetic response. Here we show that E2 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 P4. 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. E2 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 P4. 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 P4. Inhibition of mTOR by rapamycin in vivo resulted in inhibition of E2-induced protein and DNA synthesis. Proliferative diseases of the endometrium such as endometriosis and cancer are common and E2 dependent. Thus, defining this mTOR pathway suggests that local (intrauterine or peritoneal) rapamycin administration might be a therapeutic option for these diseases.
Center for the Study of Reproductive Biology and Women's Health, Departments of Developmental and Molecular Biology and.
Yuxiang
Y
Wang
Center for the Study of Reproductive Biology and Women's Health, Departments of Developmental and Molecular Biology and.
Liyin
L
Zhu
Center for the Study of Reproductive Biology and Women's Health, Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, NY 10461; and.
Satu
S
Kuokkanen
Center for the Study of Reproductive Biology and Women's Health, Departments of Developmental and Molecular Biology and Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, NY 10461; and Medical Research Council Centre for Reproductive Health, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom jeff.pollard@ed.ac.uk.
Jeffrey W
JW
Pollard
D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008954:Models, Biological; D011374:Progesterone / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects*; D011493:Protein Kinase C / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014599:Uterus / Q000166:cytology*
D047628:Estrogen Receptor alpha; D011374:Progesterone; D004958:Estradiol; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D011493:Protein Kinase C; D020123:Sirolimus
DNA synthesis; estrogen; mTOR; protein kinase C; protein synthesis