Dohi Yoshihiro, Ikura Tsuyoshi, Hoshikawa Yutaka, Katoh Yasutake, Ota Kazushige, Nakanome Ayako, Muto Akihiko, Omura Shinji, Ohta Tsutomu, Ito Akihiro, Yoshida Minoru, Noda Tetsuo, Igarashi Kazuhiko
Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryo-machi 2-1, Sendai 980-8575, Japan.
Nat Struct Mol Biol. 2008 Dec;15(12):1246-54. doi: 10.1038/nsmb.1516. Epub 2008 Nov 16.
Cellular senescence is one of the key strategies to suppress expansion of cells with mutations. Senescence is induced in response to genotoxic and oxidative stress. Here we show that the transcription factor Bach1 (BTB and CNC homology 1, basic leucine zipper transcription factor 1), which inhibits oxidative stress-inducible genes, is a crucial negative regulator of oxidative stress-induced cellular senescence. Bach1-deficient murine embryonic fibroblasts showed a propensity to undergo more rapid and profound p53-dependent premature senescence than control wild-type cells in response to oxidative stress. Bach1 formed a complex that contained p53, histone deacetylase 1 and nuclear co-repressor N-coR. Bach1 was recruited to a subset of p53 target genes and contributed to impeding p53 action by promoting histone deacetylation. Because Bach1 is regulated by oxidative stress and heme, our data show that Bach1 connects oxygen metabolism and cellular senescence as a negative regulator of p53.
细胞衰老 是抑制突变细胞增殖的关键策略之一。衰老由基因毒性和氧化应激诱导产生。在此我们表明，抑制氧化应激诱导基因的转录因子巴赫1（BTB和CNC同源物1，碱性亮氨酸拉链转录因子1）是氧化应激诱导的细胞衰老的关键负调节因子。与对照野生型细胞相比，巴赫1缺陷型小鼠胚胎成纤维细胞在氧化应激下更倾向于经历更快、更深刻的p53依赖性早衰。巴赫1形成了一个包含p53、组蛋白脱乙酰基酶1和核共抑制因子N-CoR的复合物。巴赫1被招募到一部分p53靶基因上，并通过促进组蛋白脱乙酰化来阻碍p53的作用。由于巴赫1受氧化应激和血红素调节，我们的数据表明，巴赫1作为p53的负调节因子，将氧代谢与细胞衰老联系起来。
