title: p38 mitogen-activated protein kinase stimulates estrogen-mediated transcription and proliferation through the phosphorylation and potentiation of the p160 coactivator glucocorticoid receptor-interacting protein 1.
abstract: 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 ERalpha- and ERbeta-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 ERalpha or beta, 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.
authors.affiliation: Molecular and Cellular Biology Program, Center for Bioenvironmental Research, Department of Surgery, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Frigo
authors.forename: Aninda
authors.initials: A
authors.lastname: Basu
authors.forename: Erica N
authors.initials: EN
authors.lastname: Nierth-Simpson
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Weldon
authors.forename: Christine M
authors.initials: CM
authors.lastname: Dugan
authors.forename: Steven
authors.initials: S
authors.lastname: Elliott
authors.forename: Bridgette M
authors.initials: BM
authors.lastname: Collins-Burow
authors.forename: Virgilio A
authors.initials: VA
authors.lastname: Salvo
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhu
authors.forename: Lilia I
authors.initials: LI
authors.lastname: Melnik
authors.forename: Gabriela N
authors.initials: GN
authors.lastname: Lopez
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Kushner
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Curiel
authors.forename: Brian G
authors.initials: BG
authors.lastname: Rowan
authors.forename: John A
authors.initials: JA
authors.lastname: McLachlan
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Burow
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048669:MAP Kinase Kinase 6 / Q000378:metabolism; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D007093:Imidazoles; C498001:NCOA2 protein, human; D051958:Nuclear Receptor Coactivator 2; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C400277:RWJ 67657; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human