TRAF6 Restricts p53 Mitochondrial Translocation, Apoptosis, and Tumor Suppression.
TRAF6 Restricts p53 Mitochondrial Translocation, Apoptosis, and Tumor Suppression.
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DOI：
10.1016/j.molcel.2016.10.002
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发表时间：
2016-11-17
期刊：
影响因子：
16
通讯作者：
Lin HK
中科院分区：
文献类型：
--
作者：
Zhang X;Li CF;Zhang L;Wu CY;Han L;Jin G;Rezaeian AH;Han F;Liu C;Xu C;Xu X;Huang CY;Tsai FJ;Tsai CH;Watabe K;Lin HK
线粒体p53参与细胞凋亡和肿瘤抑制。然而，它的规则没有得到很好的研究。在这里，我们表明TRAF 6 E3连接酶通过促进细胞质中K63连接的p53在K24处的遍在蛋白化，是限制p53线粒体易位和自发性细胞凋亡的关键因素，并且这种遍在蛋白化限制了p53和MCL-1/巴克之间的相互作用。遗传毒性应激通过TRAF 6从胞质溶胶到细胞核的S13/T330磷酸化依赖性易位减少了胞质溶胶中的这种泛素化，其中TRAF 6还通过招募p300进行p53乙酰化来促进核p53的K63连接的泛素化及其反式激活。在功能上，K63连接的p53泛素化损害了p53介导的细胞凋亡和肿瘤抑制。具有WT p53的结直肠癌样本揭示TRAF 6过表达与细胞凋亡负相关，并预测对化疗/放疗的不良反应。总之，我们的研究确定TRAF 6是限制p53线粒体易位的关键守门人，这种机制可能有助于肿瘤的发展和耐药性。Zhang等人发现TRAF 6通过促进细胞质中p53的K63-连接的泛素化来防止p53的线粒体易位和自发凋亡。遗传毒性应激通过TRAF 6易位到细胞核中来推翻这种保护机制。这种机制的失调可能有助于癌症的发展和对化疗和放疗的抵抗。
Mitochondrial p53 is involved in apoptosis and tumor suppression. However, its regulation is not well studied. Here, we show that TRAF6 E3 ligase is a crucial factor to restrict mitochondrial translocation of p53 and spontaneous apoptosis by promoting K63-linked ubiquitination of p53 at K24 in cytosol, and such ubiquitination limits the interaction between p53 and MCL-1/BAK. Genotoxic stress reduces this ubiquitination in cytosol by S13/T330 phosphorylation-dependent translocation of TRAF6 from cytosol to nucleus, where TRAF6 also facilitates the K63-linked ubiquitination of nuclear p53 and its transactivation by recruiting p300 for p53 acetylation. Functionally, K63-linked ubiquitination of p53 compromised p53-mediated apoptosis and tumor suppression. Colorectal cancer samples with WT p53 reveals that TRAF6 overexpression negatively correlates with apoptosis and predicts poor response to chemo/radiotherapy. Together, our study identifies TRAF6 as a critical gatekeeper to restrict p53 mitochondrial translocation and such mechanism may contribute to tumor development and drug resistance. Zhang et al discovered that TRAF6 prevents the mitochondrial translocation of p53 and spontaneous apoptosis by promoting K63-linked ubiquitination of p53 in cytosol. Genotoxic stress overrides this protection mechanism by translocating TRAF6 into nucleus. Deregulation of this mechanism may contribute to cancer development and resistance to chemotherapy and radiotherapy.
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DOI：
10.1073/pnas.0703976104
发表时间：
2007-07-10
影响因子：
11.1
作者：
Brooks, Craig;Wei, Qingqing;Dong, Zheng
通讯作者：
Dong, Zheng
影响因子：
64.5
作者：
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VOGELSTEIN, B
影响因子：
64.8
作者：
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通讯作者：
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影响因子：
8
作者：
Kokontis, JM;Wagner, AJ;Hay, N
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Hay, N
影响因子：
16
作者：
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通讯作者：
George, Donna L.