title: GCN5 regulates the activation of PI3K/Akt survival pathway in B cells exposed to oxidative stress via controlling gene expressions of Syk and Btk.
abstract: Histone acetyltransferase(s) (HATs) are involved in the acetylation of core histones, which is an important event for transcription regulation through alterations in the chromatin structure in eukaryotes. General control non-depressible 5 (GCN5) was first identified as a global coactivator and transcription-related HAT. Here we report that GCN5 regulates the activation of phosphatidylinositol 3-kinase (PI3K)/acutely transforming retrovirus AKT8 in rodent T cell lymphoma (Akt) survival pathway in B cells exposed to oxidative stress via controlling gene expressions of spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (Btk). The GCN5-deficiency remarkably caused apoptotic cell death by treatment with exogenous hydrogen peroxide (H(2)O(2)) in chicken DT40 cells. In GCN5-deficient DT40 cells, gene expressions of Syk and Btk, which are involved in activation of PI3K/Akt survival pathway in DT40 cells exposed to exogenous H(2)O(2), were remarkably decreased compared with those in wild type DT40 cells. In addition, phosphorylation of Akt in H(2)O(2)-treated GCN5-deficient cells was remarkably suppressed as compared to that of DT40. Chromatin immunoprecipitation assay revealed that GCN5 binds to proximal 5'-upstream regions of Syk and Btk genes in vivo. These results suggest that GCN5 takes part in transcriptional regulations of the Syk and Btk genes, and plays a key role in epigenetic regulation of PI3K/Akt survival pathway in B cells exposed to reactive oxygen species such as H(2)O(2).
authors.affiliation: Section of Biochemistry and Molecular Biology, Department of Medical Sciences, Miyazaki Medical College, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan. masakari@med.miyazaki-u.ac.jp
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Futoshi
authors.initials: F
authors.lastname: Kuribayashi
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Takami
authors.forename: Shinobu
authors.initials: S
authors.lastname: Imajoh-Ohmi
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Nakayama
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D002460:Cell Line; D002645:Chickens; D047369:Chromatin Immunoprecipitation; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D009154:Mutation; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis*; D000072377:Syk Kinase; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D000077329:Agammaglobulinaemia Tyrosine Kinase; D006861:Hydrogen Peroxide; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000072377:Syk Kinase; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor