Cross-talk between the estrogen receptor-, protein kinase A-, and mitogen-activated protein kinase-mediated signaling pathways in the regulation of lactotroph proliferation in primary culture.
Using pharmacological means we investigated the functional interactions between the estrogen receptor (ER)-, protein kinase A (PKA)-, and mitogen-activating protein kinase (MAPK)-mediated pathways in the regulation of lactotroph proliferation in primary culture. Treatment of lactotrophs for 28 h with the PKA inhibitor H89 or KT5720, an effective inhibitor of forskolin-induced proliferation, inhibited both insulin- and estradiol-induced proliferation. Inhibition of the MAPK activity by PD98059 or U0126 suppressed not only insulin-induced proliferation but also forskolin- and estradiol-induced proliferation. However, treatment for 28 h with the antiestrogens 4-hydroxy tamoxifen and ICI182780 failed to antagonize estradiol-induced lactotroph proliferation but instead enhanced it. Prolonging the antiestrogen treatment time from 28 to 88 h was effective in antagonizing estradiol-induced proliferation with this long-term treatment also inhibiting insulin- and forskolin-induced proliferation. There was no decrease in these mitogen-induced proliferations following treatment with a progesterone antagonist or protein kinase C inhibitor. These results suggest that cross-talk occurs between the ER-, PKA-, and MAPK-mediated signaling pathways in the regulation of lactotroph proliferation, and that antiestrogens stimulate and inhibit estradiol-induced proliferation in a time-dependent manner.
Yamakawa
Koji
K
Department of Physiology, University of Yamanashi Interdisciplinary Graduate School of Medicine and Engineering, Tamaho, Nakakoma, Yamanashi 409-3898, Japan.
Arita
Jun
J
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007328:Insulin / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D011374:Progesterone / Q000037:antagonists & inhibitors; D011388:Prolactin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020239:Receptor Cross-Talk; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D004791:Enzyme Inhibitors; D007328:Insulin; D011960:Receptors, Estrogen; D005576:Colforsin; D011374:Progesterone; D004958:Estradiol; D011388:Prolactin; D017868:Cyclic AMP-Dependent Protein Kinases