Negative control of p53 by Sir2alpha promotes cell survival under stress.
Negative control of p53 by Sir2alpha promotes cell survival under stress.
复制标题
DOI：
--
复制
发表时间：
2001
期刊：
影响因子：
64.5
通讯作者：
J. Luo;A. Nikolaev;S. Imai;D. Chen;F. Su;A. Shiloh;L. Guarente;W. Gu
中科院分区：
文献类型：
--
作者：
J. Luo;A. Nikolaev;S. Imai;D. Chen;F. Su;A. Shiloh;L. Guarente;W. Gu
在酵母中，nad依赖的Sir2组蛋白去乙酰化将细胞代谢与基因沉默以及衰老联系起来。在这里，我们发现哺乳动物Sir2alpha与p53物理相互作用并减弱p53介导的功能。烟酰胺（维生素B3）抑制Sir2alpha诱导的nad依赖性p53去乙酰化，并在体内提高p53乙酰化水平。此外，Sir2alpha在DNA损伤和氧化应激反应中抑制p53依赖性细胞凋亡，而Sir2alpha点突变体的表达增加了细胞在应激反应中的敏感性。因此，我们的发现暗示了哺乳动物Sir2alpha介导的p53调控途径。这些结果对Sir2alpha在p53依赖性凋亡反应中调节细胞敏感性的重要作用以及在癌症治疗中的可能作用具有重要意义。
The NAD-dependent histone deacetylation of Sir2 connects cellular metabolism with gene silencing as well as aging in yeast. Here, we show that mammalian Sir2alpha physically interacts with p53 and attenuates p53-mediated functions. Nicotinamide (Vitamin B3) inhibits an NAD-dependent p53 deacetylation induced by Sir2alpha, and also enhances the p53 acetylation levels in vivo. Furthermore, Sir2alpha represses p53-dependent apoptosis in response to DNA damage and oxidative stress, whereas expression of a Sir2alpha point mutant increases the sensitivity of cells in the stress response. Thus, our findings implicate a p53 regulatory pathway mediated by mammalian Sir2alpha. These results have significant implications regarding an important role for Sir2alpha in modulating the sensitivity of cells in p53-dependent apoptotic response and the possible effect in cancer therapy.