AMPK couples p73 with p53 in cell fate decision
AMPK couples p73 with p53 in cell fate decision
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DOI：
10.1038/cdd.2014.60
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发表时间：
2014-09-01
影响因子：
12.4
通讯作者：
Shaul, Y.
中科院分区：
文献类型：
--
作者：
Adamovich, Y.;Adler, J.;Shaul, Y.
p53蛋白家族在响应不同类型的应激（例如DNA损伤、缺氧或致癌应激）而决定细胞命运方面具有重要作用。近年来，p53也被证明对代谢应激有反应，并被AMP激活的蛋白激酶（AMPK）诱导，AMPK是一种中央细胞能量传感器。生物信息学分析揭示了p53肿瘤抑制基因p73中三个假定的AMPK磷酸化位点。在体外和体内试验证实，AMPK磷酸化p73的一个新的残基，S426。在细胞中AMPK的特异性药理学刺激后，p73蛋白半衰期延长，导致p73在细胞核中积累。我们发现，p73逃避E3连接酶Itch导致减少p73泛素化和蛋白酶体降解。此外，AMPK的慢性激活导致p73依赖性的凋亡，但仅在p53表达细胞中。令人惊讶的是，我们发现p73是AMPK激活下p53稳定和积累所必需的，但在DNA损伤下是不稳定的。我们的研究结果夫妇p73与p53在决定细胞命运下AMPK诱导的代谢应激。
The p53 family of proteins has an important role in determining cell fate in response to different types of stress, such as DNA damage, hypoxia, or oncogenic stress. In recent years, p53 has also been shown to respond to metabolic stress, and to be induced by the AMP-activated protein kinase (AMPK), a central cellular energy sensor. A bioinformatic analysis revealed three putative AMPK phopshorylation sites in p73, a p53 tumor suppressor paralog. In vitro and in vivo assays confirmed that AMPK phosphorylates p73 on a novel residue, S426. Following specific pharmacologic stimulation of AMPK in cells, p73 protein half-life was prolonged leading to p73 accumulation in the nucleus. We show that p73 escaped the E3 ligase Itch resulting in reduced p73 ubiquitination and proteasomal degradation. Furthermore, chronic activation of AMPK led to apoptosis that was p73 dependent, but only in p53-expressing cells. Surprisingly, we found that p73 was required for p53 stabilization and accumulation under AMPK activation, but was dispensable under DNA damage. Our findings couple p73 with p53 in determining cell fate under AMPK-induced metabolic stress.