AMP-activated protein kinase induces a p53-dependent metabolic checkpoint
AMP-activated protein kinase induces a p53-dependent metabolic checkpoint
复制标题
DOI：
10.1016/j.molcel.2005.03.027
复制
发表时间：
2005-04-29
期刊：
影响因子：
16
通讯作者：
Thompson, CB
中科院分区：
文献类型：
--
作者：
Jones, RG;Plas, DR;Thompson, CB
复制性细胞分裂是一个需要能量的过程，只有当细胞有足够的代谢资源来支持细胞质量加倍时才能执行。在这里，我们表明，增殖的哺乳动物细胞有一个细胞周期检查点，响应葡萄糖的可用性。葡萄糖依赖性检查点发生在G（1）/S边界，并由AMP活化蛋白激酶（AMPK）调节。这种细胞周期停滞发生，尽管持续的氨基酸可用性和活性mTOR。AMPK激活诱导p53在丝氨酸15上的磷酸化，并且这种磷酸化是启动AMPK依赖性细胞周期停滞所必需的。AMPK诱导的p53激活促进细胞对葡萄糖剥夺的反应，并且已经经历p53依赖性代谢停滞的细胞可以在葡萄糖恢复后迅速重新进入细胞周期。然而，AMPK的持续激活导致p53依赖性细胞衰老加速。因此，AMPK是细胞周期的细胞内在调节剂，其协调细胞增殖与碳源可用性。
Replicative cell division is an energetically demanding process that can be executed only if cells have sufficient metabolic resources to support a doubling of cell mass. Here we show that proliferating mammalian cells have a cell-cycle checkpoint that responds to glucose availability. The glucose-dependent checkpoint occurs at the G(1)/S boundary and is regulated by AMP-activated protein kinase (AMPK). This cell-cycle arrest occurs despite continued amino acid availability and active mTOR. AMPK activation induces phosphorylation of p53 on serine 15, and this phosphorylation is required to initiate AMPK-dependent cellcycle arrest. AMPK-Induced p53 activation promotes cellular survival in response to glucose deprivation, and cells that have undergone a p53-dependent metabolic arrest can rapidly reenter the cell-cycle upon glucose restoration. However, persistent activation of AMPK leads to accelerated p53-dependent cellular senescence. Thus, AMPK is a cell-intrinsic regulator of the cell-cycle that coordinates cellular proliferation with carbon source availability.