Progestin activation of nongenomic pathways via cross talk of progesterone receptor with estrogen receptor beta induces proliferation of endometrial stromal cells.
Uterine decidualization is characterized by stromal cell proliferation and differentiation, which are controlled by ovarian hormones estradiol and progesterone. Here we report that the proliferative response of UIII rat uterine stromal cells to a short treatment with progestins requires active progesterone receptor (PR) and estrogen receptor beta (ERbeta) as well as a rapid and transient activation of Erk1-2 and Akt signaling. The optimal R5020 concentration for the proliferative response as well as for activation of the signaling cascades was between 10 and 100 pm. UIII cells are negative for ERalpha and have low levels of ERbeta and PR located mainly in the cytoplasm. Upon progestin treatment PR translocated to the cell nucleus where it colocalized with activated Erk1-2. Neither progestins nor estradiol transactivated the corresponding transfected reporter genes, suggesting that endogenous PR and ERbeta are transcriptionally incompetent. A fraction of endogenous PR and ERbeta form a complex as demonstrated by coimmunoprecipitation. Taken together, our results suggest that the proliferative response of uterine stromal cells to picomolar concentrations of progestins does not require direct transcriptional effects and is mediated by activation of the Erk1-2 and Akt signaling pathways via cross talk between PR and ERbeta.
Vallejo
Griselda
G
Instituto de Biología y Medicina Experimental (IBYME-CONICET), Obligado 2490, (1428) Buenos Aires, Argentina.
Ballaré
Cecilia
C
Barañao
José Lino
JL
Beato
Miguel
M
Saragüeta
Patricia
P
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D049109:Cell Proliferation; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D004717:Endometrium / Q000166:cytology / Q000187:drug effects*; D004789:Enzyme Activation; D047628:Estrogen Receptor alpha / Q000235:genetics; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D017930:Genes, Reporter; D016678:Genome; D019950:Mitogen-Activated Protein Kinase 1 / Q000032:analysis / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000032:analysis / Q000378:metabolism; D009154:Mutation; D011372:Progestins / Q000494:pharmacology*; D011397:Promegestone / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis / Q000378:metabolism; D051381:Rats; D011980:Receptors, Progesterone / Q000032:analysis / Q000378:metabolism*; D015398:Signal Transduction; D017154:Stromal Cells / Q000187:drug effects; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011372:Progestins; D011980:Receptors, Progesterone; D011397:Promegestone; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3