Induction of progesterone target genes requires activation of Erk and Msk kinases and phosphorylation of histone H3.
How genes are regulated in the context of chromatin is a central question of biology. Steroid hormones control gene expression via interaction of their receptors with target sequences on DNA but can also activate cytoplasmic signaling cascades. Here we report that rapid Erk activation by progestins participates in induction of target genes by preparing the chromatin for transcription. Five minutes after hormone treatment, Erk activation leads to phosphorylation of the progesterone receptor (PR), activation of Msk1, and recruitment of a complex of the three proteins to a nucleosome on the MMTV promoter. Msk1 phosphorylates histone H3, leading to displacement of HP1gamma and recruitment of Brg1 and RNA polymerase II. Cell-free experiments show a direct interaction between PR, Erk, and Msk1 and support the importance of H3 phosphorylation for nucleosome remodeling. Inhibition of Msk1 activation blocks recruitment of the kinase complex, H3 phosphorylation, and HP1gamma displacement, thus precluding remodeling and induction of the promoter.
Vicent
Guillermo P
GP
Centre de Regulació Genòmica, Universitat Pompeu Fabra, Parc de Recerca Biomèdica, Dr. Aiguader 88, E-08003 Barcelona, Spain.
Ballaré
Cecilia
C
Nacht
A Silvina
AS
Clausell
Jaime
J
Subtil-Rodríguez
Alicia
A
Quiles
Ignacio
I
Jordan
Albert
A
Beato
Miguel
M
D000818:Animals; D002474:Cell-Free System; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D008745:Methylation / Q000187:drug effects; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009707:Nucleosomes / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011372:Progestins / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D012319:RNA Polymerase II / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013379:Substrate Specificity; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured
C453799:Cbx3 protein, mouse; D002868:Chromosomal Proteins, Non-Histone; D004791:Enzyme Inhibitors; D006657:Histones; D009707:Nucleosomes; D011372:Progestins; D011980:Receptors, Progesterone; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors; D012694:Serine; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D012319:RNA Polymerase II; D008239:Lysine