Section of Biochemistry and Molecular Biology, Department of Medical Sciences, Miyazaki Medical College, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan.
Biochem Biophys Res Commun. 2011 Feb 25;405(4):657-61. doi: 10.1016/j.bbrc.2011.01.088. Epub 2011 Jan 31.
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).
组蛋白乙酰转移酶（HATs）参与核心组蛋白的乙酰化，这是真核生物中通过改变染色质结构进行转录调控的重要事件。一般控制非抑制 5（GCN5）最初被鉴定为一种全局共激活因子和转录相关的 HAT。在这里，我们报告 GCN5 通过控制脾酪氨酸激酶（Syk）和布鲁顿酪氨酸激酶（Btk）的基因表达，调节氧化应激下 B 细胞中磷脂酰肌醇 3-激酶（PI3K）/急性转化逆转录病毒 AKT8（Akt）存活途径的激活。在外源性过氧化氢（H2O2）处理下，GCN5 缺陷鸡 DT40 细胞中明显发生凋亡细胞死亡。在 GCN5 缺陷型 DT40 细胞中，与野生型 DT40 细胞相比，在外源性 H2O2 处理下，参与 DT40 细胞中 PI3K/Akt 存活途径激活的 Syk 和 Btk 的基因表达明显降低。此外，与 DT40 相比，H2O2 处理的 GCN5 缺陷细胞中 Akt 的磷酸化明显受到抑制。染色质免疫沉淀试验表明，GCN5 在体内与 Syk 和 Btk 基因的近端 5'-上游区域结合。这些结果表明，GCN5 参与 Syk 和 Btk 基因的转录调控，在 B 细胞中对 PI3K/Akt 存活途径的表观遗传调控中发挥关键作用，B 细胞暴露于活性氧如 H2O2 中。
