Cop1 constitutively regulates c-Jun protein stability and functions as a tumor suppressor in mice
Cop1 constitutively regulates c-Jun protein stability and functions as a tumor suppressor in mice
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DOI：
10.1172/jci45784
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发表时间：
2011-04-01
影响因子：
15.9
通讯作者：
Marine, Jean-Christophe
中科院分区：
文献类型：
--
作者：
Migliorini, Domenico;Bogaerts, Sven;Marine, Jean-Christophe
生化研究表明E3泛素连接酶组成型光形态发生蛋白1（Cop 1;也称为Rfwd 2）在肿瘤发生中的相互冲突的作用，为癌蛋白c-Jun和肿瘤抑制因子p53作为其靶点提供了证据。在这里，我们提出了我们认为是第一次在体内调查的作用，Cop 1在癌症病因学。使用一种创新的遗传方法来产生Cop 1的等位基因系列，我们发现Cop 1亚型小鼠在生命的第一年自发地以高频率发生恶性肿瘤，并且对辐射诱导的淋巴瘤非常敏感。进一步的分析表明，c-Jun是Cop 1的关键生理靶点，Cop 1在体内组成性地将c-Jun保持在低水平，从而调节c-Jun/AP-1转录活性。重要的是，Cop 1缺陷刺激细胞增殖的c-Jun依赖性的方式。在几种癌症类型中以显著的频率观察到COP 1的局灶性缺失，并且确定COP 1缺失是导致人类癌症中c-Jun上调的机制之一。因此，我们得出结论，Cop 1是一种肿瘤抑制因子，其功能，至少部分，通过拮抗c-Jun致癌活性。在缺乏Cop 1和p53之间遗传相互作用的证据的情况下，我们的数据强烈反对使用Cop 1抑制药物进行癌症治疗。
Biochemical studies have suggested conflicting roles for the E3 ubiquitin ligase constitutive photomorphogenesis protein 1 (Cop 1; also known as Rfwd2) in tumorigenesis, providing evidence for both the oncoprotein c-Jun and the tumor suppressor p53 as its targets. Here we present what we believe to be the first in vivo investigation of the role of Cop1 in cancer etiology. Using an innovative genetic approach to generate an allelic series of Cop1, we found that Cop1 hypomorphic mice spontaneously developed malignancy at a high frequency in the first year of life and were highly susceptible to radiation-induced lymphomagenesis. Further analysis revealed that c-Jun was a key physiological target for Cop1 and that Cop1 constitutively kept c-Jun at low levels in vivo and thereby modulated c-Jun/AP-1 transcriptional activity. Importantly, Cop1 deficiency stimulated cell proliferation in a c-Jun-dependent manner. Focal deletions of COP1 were observed at significant frequency across several cancer types, and COP1 loss was determined to be one of the mechanisms leading to c-Jun upregulation in human cancer. We therefore conclude that Cop1 is a tumor suppressor that functions, at least in part, by antagonizing c-Jun oncogenic activity. In the absence of evidence for a genetic interaction between Cop1 and p53, our data strongly argue against the use of Cop1-inhibitory drugs for cancer therapy.