Redox-sensitive cysteines bridge p300/CBP-mediated acetylation and FoxO4 activity
Redox-sensitive cysteines bridge p300/CBP-mediated acetylation and FoxO4 activity
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DOI：
10.1038/nchembio.194
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发表时间：
2009-09-01
影响因子：
14.8
通讯作者：
Burgering, Boudewijn M. T.
中科院分区：
文献类型：
--
作者：
Dansen, Tobias B.;Smits, Lydia M. M.;Burgering, Boudewijn M. T.
由活性氧引起的细胞损伤在癌症和衰老的病理生物学中起着关键作用。FoxO转录因子参与多种细胞过程，包括细胞周期调控、细胞凋亡和对活性氧的抵抗，动物模型研究表明，这些转录因子在抑制肿瘤、维持干细胞和延长寿命方面起着至关重要的作用。在这里，我们报道了人类细胞中FoxO的活性是由细胞的氧化还原状态通过一种独特的信号转导机制直接调节的。我们发现，活性氧物种诱导FoxO和p300/CBP乙酰基转移酶形成依赖于半胱氨酸-硫醇二硫键的复合体，而p300/CBP介导的乙酰化对FoxO生物活性的调节完全依赖于这种氧化还原依赖复合体的形成。这些发现直接将细胞的氧化还原状态与长寿蛋白FoxO的活性联系起来。
Cellular damage invoked by reactive oxygen species plays a key role in the pathobiology of cancer and aging. Forkhead box class O (FoxO) transcription factors are involved in various cellular processes including cell cycle regulation, apoptosis and resistance to reactive oxygen species, and studies in animal models have shown that these transcription factors are of vital importance in tumor suppression, stem cell maintenance and lifespan extension. Here we report that the activity of FoxO in human cells is directly regulated by the cellular redox state through a unique mechanism in signal transduction. We show that reactive oxygen species induce the formation of cysteine-thiol disulfide-dependent complexes of FoxO and the p300/CBP acetyltransferase, and that modulation of FoxO biological activity by p300/CBP-mediated acetylation is fully dependent on the formation of this redox-dependent complex. These findings directly link cellular redox status to the activity of the longevity protein FoxO.