TY - JOUR
T1 - p38 mitogen-activated protein kinase stimulates estrogen-mediated transcription and proliferation through the phosphorylation and potentiation of the p160 coactivator glucocorticoid receptor-interacting protein
AU - Frigo, Daniel E.
AU - Basu, Aninda
AU - Nierth-Simpson, Erica N.
AU - Weldon, Christopher B.
AU - Dugan, Christine M.
AU - Elliott, Steven
AU - Collins-Burow, Bridgette M.
AU - Salvo, Virgilio A.
AU - Zhu, Yun
AU - Melnik, Lilia I.
AU - Lopez, Gabriela N.
AU - Kushner, Peter J.
AU - Curiel, Tyler J.
AU - Rowan, Brian G.
AU - McLachlan, John A.
AU - Burow, Matthew E.
PY - 2006/5
Y1 - 2006/5
N2 - Nuclear hormone receptors, such as the estrogen receptors (ERs), are regulated by specific kinase signaling pathways. Here, we demonstrate that the p38 MAPK stimulates both ERα- and ERβ-mediated transcription in MCF-7 breast carcinoma, Ishikawa endometrial adenocarcinoma, and human embryonic kidney 293 cells. Inhibition of this potentiation using the p38 inhibitor, RWJ67657, blocked estrogen-mediated transcription and proliferation. Activated ERs promote gene expression in part through the recruitment of the p160 class of coactivators. Because no direct p38 phosphorylation sites have been determined on either ERα or β, we hypothesized that p38 could target the p160 class of coactivators. We show for the first time using pharmacological and molecular techniques that the p160 coactivator glucocorticoid receptor-interacting protein 1 (GRIP1) is phosphorylated and potentiated by the p38 MAPK signaling cascade in vitro and in vivo. S736 was identified as a necessary site for p38 induction of GRIP1 transcriptional activation. The C terminus of GRIP1 was also demonstrated to contain a p38-responsive region. Taken together, these results indicate that p38 stimulates ER-mediated transcription by targeting the GRIP1 coactivator.
AB - Nuclear hormone receptors, such as the estrogen receptors (ERs), are regulated by specific kinase signaling pathways. Here, we demonstrate that the p38 MAPK stimulates both ERα- and ERβ-mediated transcription in MCF-7 breast carcinoma, Ishikawa endometrial adenocarcinoma, and human embryonic kidney 293 cells. Inhibition of this potentiation using the p38 inhibitor, RWJ67657, blocked estrogen-mediated transcription and proliferation. Activated ERs promote gene expression in part through the recruitment of the p160 class of coactivators. Because no direct p38 phosphorylation sites have been determined on either ERα or β, we hypothesized that p38 could target the p160 class of coactivators. We show for the first time using pharmacological and molecular techniques that the p160 coactivator glucocorticoid receptor-interacting protein 1 (GRIP1) is phosphorylated and potentiated by the p38 MAPK signaling cascade in vitro and in vivo. S736 was identified as a necessary site for p38 induction of GRIP1 transcriptional activation. The C terminus of GRIP1 was also demonstrated to contain a p38-responsive region. Taken together, these results indicate that p38 stimulates ER-mediated transcription by targeting the GRIP1 coactivator.
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U2 - 10.1210/me.2004-0075
DO - 10.1210/me.2004-0075
M3 - Article
C2 - 16410316
AN - SCOPUS:33746472300
SN - 0888-8809
VL - 20
SP - 971
EP - 983
JO - Molecular Endocrinology
JF - Molecular Endocrinology
IS - 5
ER -