title: The p38 SAPK is recruited to chromatin via its interaction with transcription factors.
abstract: In mammals, the stress-activated protein kinase (SAPK) p38 coordinates a rapid and complex transcriptional program to adapt to sudden changes in the extracellular environment. Although a number of genes have been reported to be under the control of p38, the basic mechanisms of transcriptional regulation by this SAPK remain uncharacterized. Here we show that in response to osmotic shock, anisomycin- or TNFα-activated p38 SAPK is recruited to stress-induced genes. The MAPKK MKK6 is also found at stress-responsive promoters. The recruitment of RNA polymerase II complex to the target promoters requires p38 activity. Moreover, when tethered to DNA as a LexA fusion protein, p38 activates transcription in a stress-regulated manner. Thus, p38 activity allows for recruitment of RNA polymerase and transcription initiation. p38 directly phosphorylates and interacts with the transcription factor Elk1. p38 activity is necessary for the recruitment of Elk1 to the c-Fos promoter, and knocking down Elk1 by siRNAs compromises both p38 recruitment to the c-Fos promoter and c-Fos transcriptional up-regulation upon osmostress. In addition, p38 recruitment to the osmoinducible gene Cox2 and the TNFα target gene IL8 is mediated by the transcription factors AP1 and NFκB, respectively. Therefore, anchoring of active SAPK to target genes is mediated by transcription factors. The presence of active p38 at open reading frames also suggests the involvement of the SAPK in elongation. Taken together, SAPK recruitment to target genes appears to be a broad mechanism to regulate transcription that has been preserved from yeast to mammals.
authors.affiliation: Cell Signalling Research Group, Departament de Ciències Experimetals i de la Salut, Universitat Pompeu Fabra, Dr Aiguader 88, 08003 Barcelona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Ferreiro
authors.forename: Montserrat
authors.initials: M
authors.lastname: Barragan
authors.forename: Albert
authors.initials: A
authors.lastname: Gubern
authors.forename: Esteban
authors.initials: E
authors.lastname: Ballestar
authors.forename: Manel
authors.initials: M
authors.lastname: Joaquin
authors.forename: Francesc
authors.initials: F
authors.lastname: Posas
mesh_terms: D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D048669:MAP Kinase Kinase 6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D009997:Osmotic Pressure / Q000187:drug effects / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C508606:CXCL8 protein, human; D002843:Chromatin; C494112:ELK1 protein, human; C494113:Elk1 protein, mouse; D016209:Interleukin-8; D016328:NF-kappa B; D019384:Nucleic Acid Synthesis Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D050807:ets-Domain Protein Elk-1; D000841:Anisomycin; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human; C482567:Map2k6 protein, mouse; D012319:RNA Polymerase II