title: Mitogen- and stress-activated protein kinases 1 and 2 are required for maximal trefoil factor 1 induction.
abstract: Mitogen- and stress-activated protein kinases 1 and 2 (MSK1 and MSK2), activated downstream of the ERK- and p38-mitogen-activated protein kinase pathways are involved in cell survival, proliferation and differentiation. Following mitogenic or stress stimuli, they mediate the nucleosomal response, which includes phosphorylation of histone H3 at serine 10 (H3S10ph) coupled with transcriptional activation of immediate-early genes. While MSK1 and MSK2 are closely related, their relative roles may vary with cellular context and/or stimuli. However, our knowledge of MSK2 recruitment to immediate-early genes is limited, as research has primarily focused on MSK1. Here, we demonstrate that both MSK1 and MSK2, regulate the phorbol ester 12-O-tetradecanoylphorbol-13-acetate induced expression of the breast cancer marker gene, trefoil factor 1 (TFF1), by phosphorylating H3S10 at its 5' regulatory regions. The MSK-mediated phosphorylation of H3S10 promotes the recruitment of 14-3-3 isoforms and BRG1, the ATPase subunit of the BAF/PBAF remodeling complex, to the enhancer and upstream promoter elements of TFF1. The recruited chromatin remodeling activity leads to the RNA polymerase II carboxy-terminal domain phosphorylation at the TFF1 promoter, initiating TFF1 expression in MCF-7 breast cancer cells. Moreover, we show that MSK1 or MSK2 is recruited to TFF1 regulatory regions, but as components of different multiprotein complexes.
authors.affiliation: Manitoba Institute of Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Protiti
authors.initials: P
authors.lastname: Khan
authors.forename: Bojan
authors.initials: B
authors.lastname: Drobic
authors.forename: Beatriz
authors.initials: B
authors.lastname: Pérez-Cadahía
authors.forename: Shannon
authors.initials: S
authors.lastname: Healy
authors.forename: Shihua
authors.initials: S
authors.lastname: He
authors.forename: James R
authors.initials: JR
authors.lastname: Davie
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism; D024506:5' Flanking Region; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009707:Nucleosomes / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D006657:Histones; D009687:Nuclear Proteins; D009707:Nucleosomes; C051838:TFF1 protein, human; D014157:Transcription Factors; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; C020922:4-O-methyl-12-O-tetradecanoylphorbol 13-acetate; C115634:RPS6KA4 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D012319:RNA Polymerase II; C084108:SMARCA4 protein, human; D004265:DNA Helicases; D013755:Tetradecanoylphorbol Acetate