组蛋白去乙酰化酶抑制剂通过Sp1依赖途径预防氧化性神经元死亡，且与多聚谷氨酰胺重复序列扩增无关。
Histone deacetylase inhibitors prevent oxidative neuronal death independent of expanded polyglutamine repeats via an Sp1-dependent pathway.
作者信息
Ryu Hoon, Lee Junghee, Olofsson Beatrix A, Mwidau Aziza, Dedeoglu Alpaslan, Escudero Maria, Flemington Erik, Azizkhan-Clifford Jane, Ferrante Robert J, Ratan Rajiv R
机构信息
Department of Neurology and Program in Neuroscience, Harvard Medical School and Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, MA 02115, USA.
出版信息
Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4281-6. doi: 10.1073/pnas.0737363100. Epub 2003 Mar 14.
Abstract
Oxidative stress is believed to be an important mediator of neurodegeneration. However, the transcriptional pathways induced in neurons by oxidative stress that activate protective gene responses have yet to be fully delineated. We report that the transcription factor Sp1 is acetylated in response to oxidative stress in neurons. Histone deacetylase (HDAC) inhibitors augment Sp1 acetylation, Sp1 DNA binding, and Sp1-dependent gene expression and confer resistance to oxidative stress-induced death in vitro and in vivo. Sp1 activation is necessary for the protective effects of HDAC inhibitors. Together, these results demonstrate that HDAC inhibitors inhibit oxidative death independent of polyglutamine expansions by activating an Sp1-dependent adaptive response.
摘要
氧化应激被认为是神经退行性变的重要介导因素。然而，氧化应激在神经元中诱导激活保护性基因反应的转录途径尚未完全阐明。我们报告，转录因子Sp1在神经元中因氧化应激而发生乙酰化。组蛋白脱乙酰酶（HDAC）抑制剂可增强Sp1乙酰化、Sp1与DNA的结合以及Sp1依赖性基因表达，并在体外和体内赋予对氧化应激诱导死亡的抗性。Sp1激活对于HDAC抑制剂的保护作用是必需的。这些结果共同表明，HDAC抑制剂通过激活Sp1依赖性适应性反应来抑制氧化死亡，而与多聚谷氨酰胺扩增无关。
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