GRAMD4 mimics p53 and mediates the apoptotic function of p73 at mitochondria
GRAMD4 mimics p53 and mediates the apoptotic function of p73 at mitochondria
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DOI：
10.1038/cdd.2010.153
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发表时间：
2011-05-01
影响因子：
12.4
通讯作者：
Puetzer, B. M.
中科院分区：
文献类型：
--
作者：
John, K.;Alla, V.;Puetzer, B. M.
p73是p53家族的一员，与p53具有高度的序列同源性，并表现出许多类似p53的特性：结合p53- dna靶位点，激活p53应答基因，诱导细胞周期阻滞和凋亡。除了这种转录依赖作用外，我们对p73在线粒体中控制细胞命运的下游机制知之甚少。我们之前已经发现GRAMD4（别名KIAA0767或死亡诱导蛋白）是E2F1的一个新的p53独立的促凋亡靶标，它定位于线粒体。在本研究中，我们发现p73诱导的细胞凋亡是通过GRAMD4的表达和线粒体易位介导的。我们发现该蛋白与Bcl-2物理相互作用，促进Bax线粒体重定位和寡聚化，并高效诱导线粒体膜渗透，释放细胞色素c和Smac。p73 α和p73 β亚型的过表达，而不是p53的过表达，导致GRAMD4启动子直接反激活。此外，GRAMD4诱导Bcl-2和Bax蛋白水平的变化。在顺铂（cDDP）作用下，GRAMD4转录以依赖内源性p73的方式被激活。在异种实体瘤移植中，GRAMD4和cDDP的异位表达可增强肿瘤杀伤。我们的研究结果表明，p73能够通过一种新的机制，以促凋亡的GRAMD4为介质，通过线粒体途径触发细胞凋亡，并强烈支持其p53样功能。细胞死亡与分化（2011）18,874-886；doi: 10.1038 / cdd.2010.153;2010年12月3日在线发布
p73, a member of the p53 family, shares high sequence homology with p53 and shows many p53-like properties: it binds to p53-DNA target sites, transactivates p53-responsive genes and induces cell cycle arrest and apoptosis. Apart from this transcription-dependent effect, less is known about the downstream mechanism(s) by which p73 controls cell fate at the mitochondria. We have previously identified GRAMD4 (alias KIAA0767 or Death-Inducing-Protein) as a novel p53-independent pro-apoptotic target of E2F1, which localizes to mitochondria. In this study, we found that p73-induced apoptosis is mediated by GRAMD4 expression and translocation to the mitochondria. We showed that this protein physically interacts with Bcl-2, promotes Bax mitochondrial relocalization and oligomerization, and is highly efficient in inducing mitochondrial membrane permeabilization with release of cytochrome c and Smac. Overexpression of p73 alpha and p73 beta isoforms, but not p53, leads to direct GRAMD4 promoter transactivation. In addition, GRAMD4 induces changes in Bcl-2 and Bax protein levels. GRAMD4 transcription is activated in response to cisplatin (cDDP) in a manner dependent on endogenous p73. Using solid tumor xenografts, ectopic expression of GRAMD4 together with cDDP resulted in enhanced cancer killing. Our findings demonstrate that p73 is able to trigger apoptosis via the mitochondrial pathway by a new mechanism using pro-apoptotic GRAMD4 as mediator, and strongly support its p53-like function. Cell Death and Differentiation (2011) 18, 874-886; doi:10.1038/cdd.2010.153; published online 3 December 2010