title: p38 MAPK enhances STAT1-dependent transcription independently of Ser-727 phosphorylation.
abstract: The transcription factor signal transducer and activator of transcription 1 (STAT1) requires phosphorylation at both Tyr-701 and Ser-727 for full activation. IFN-gamma induces phosphorylation of both residues, whereas stress signals like UV or lipopolysaccharide stimulate phosphorylation of Ser-727 only. Using p38alpha mitogen-activated protein kinase (MAPK)-deficient cells, we show that the stress-induced phosphorylation of Ser-727 requires p38alpha MAPK activity, whereas IFN-gamma-stimulated Ser-727 phosphorylation occurs independently of the p38alpha pathway. Consistently, IFN-gamma stimulated expression of the STAT1 target gene IRF1 to a similar extent in both wild-type and p38alpha-deficient cells. However, stress-induced activation of the p38 MAPK pathway considerably enhanced the IFN-gamma-induced expression of both the endogenous IRF1 gene and a reporter driven by the IFN-gamma-activated sequence element of the IRF1 promoter. This enhancement occurred independently of increased phosphorylation of Ser-727 by the p38 pathway. Taken together, these results demonstrate an interaction between IFN-gamma signaling and the p38 pathway that leads to increased transcriptional activation by STAT1 independently of phosphorylation at Ser-727.
authors.affiliation: Vienna Biocenter, Institute of Microbiology and Genetics, Dr. Bohr-Gasse 9, A-1030 Vienna, Austria.
authors.forename: Katrin
authors.initials: K
authors.lastname: Ramsauer
authors.forename: Iwona
authors.initials: I
authors.lastname: Sadzak
authors.forename: Almudena
authors.initials: A
authors.lastname: Porras
authors.forename: Andreas
authors.initials: A
authors.lastname: Pilz
authors.forename: Angel R
authors.initials: AR
authors.lastname: Nebreda
authors.forename: Thomas
authors.initials: T
authors.lastname: Decker
authors.forename: Pavel
authors.initials: P
authors.lastname: Kovarik
mesh_terms: D016475:3T3 Cells; D000818:Animals; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004268:DNA-Binding Proteins; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D012694:Serine; D007371:Interferon-gamma; D008156:Luciferases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases