The ubiquitin ligase COP1 is a critical negative regulator of p53
The ubiquitin ligase COP1 is a critical negative regulator of p53
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DOI：
10.1038/nature02514
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发表时间：
2004-05-06
期刊：
影响因子：
64.8
通讯作者：
Dixit, VM
中科院分区：
文献类型：
--
作者：
Dornan, D;Wertz, I;Dixit, VM
COP 1（constitutively photomorphogenic 1）是一种抑制植物光形态建成（photomorphogenesis）的蛋白质。COP 1的突变体是组成型光形态发生的，这归因于它们不能负调节蛋白质LAF 1（参考文献1）和HY 5（参考文献2）。COP 1在哺乳动物细胞中的作用不太清楚（3）。在这里，我们确定肿瘤抑制蛋白p53作为COP 1相互作用蛋白。COP 1通过靶向p53以泛素依赖性方式被蛋白酶体降解来增加p53的周转，而不依赖于已知与p53相互作用并负调节p53的MDM 2或Pirh 2。此外，COP 1在体外和体内充当p53的E3泛素连接酶，并抑制p53依赖性转录和凋亡。通过短干扰RNA（siRNA）消耗COP 1稳定p53并将细胞阻滞在细胞周期的G1期。此外，我们确定COP 1作为p53诱导基因，并表明，COP 1和MDM 2的siRNA协同消耗敏感U2-OS细胞电离辐射诱导的细胞死亡。总体而言，这些结果表明，COP 1是p53的关键负调节因子，代表了在未应激细胞中将p53维持在低水平的新途径。
COP1 ( constitutively photomorphogenic 1) is a RING-finger-containing protein that functions to repress plant photomorphogenesis, the light-mediated programme of plant development. Mutants of COP1 are constitutively photomorphogenic, and this has been attributed to their inability to negatively regulate the proteins LAF1 (ref. 1) and HY5 ( ref. 2). The role of COP1 in mammalian cells is less well characterized(3). Here we identify the tumour-suppressor protein p53 as a COP1-interacting protein. COP1 increases p53 turnover by targeting it for degradation by the proteasome in a ubiquitin-dependent fashion, independently of MDM2 or Pirh2, which are known to interact with and negatively regulate p53. Moreover, COP1 serves as an E3 ubiquitin ligase for p53 in vitro and in vivo, and inhibits p53-dependent transcription and apoptosis. Depletion of COP1 by short interfering RNA ( siRNA) stabilizes p53 and arrests cells in the G1 phase of the cell cycle. Furthermore, we identify COP1 as a p53-inducible gene, and show that the depletion of COP1 and MDM2 by siRNA cooperatively sensitizes U2-OS cells to ionizing-radiation-induced cell death. Overall, these results indicate that COP1 is a critical negative regulator of p53 and represents a new pathway for maintaining p53 at low levels in unstressed cells.