Dansen Tobias B, Smits Lydia M M, van Triest Miranda H, de Keizer Peter L J, van Leenen Dik, Koerkamp Marian Groot, Szypowska Anna, Meppelink Amanda, Brenkman Arjan B, Yodoi Junji, Holstege Frank C P, Burgering Boudewijn M T
Department of Physiological Chemistry, University Medical Center Utrecht, Utrecht, The Netherlands.
Nat Chem Biol. 2009 Sep;5(9):664-72. doi: 10.1038/nchembio.194. Epub 2009 Aug 2.
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.
活性氧引发的细胞损伤在癌症和衰老的病理生物学中起关键作用。叉头框O类（FoxO）转录因子参与包括细胞周期调控、细胞凋亡和对活性氧的抗性等各种细胞过程，动物模型研究表明这些转录因子在肿瘤抑制、干细胞维持和寿命延长中至关重要。在此我们报告，人类细胞中FoxO的活性通过信号转导中的独特机制直接受细胞氧化还原状态调控。我们表明活性氧诱导FoxO与p300/CBP乙酰转移酶形成半胱氨酸-硫醇二硫键依赖性复合物，并且p300/CBP介导的乙酰化对FoxO生物学活性的调节完全依赖于这种氧化还原依赖性复合物的形成。这些发现直接将细胞氧化还原状态与长寿蛋白FoxO的活性联系起来。
