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The ubiquitin ligase COP1 is a critical negative regulator of p53

机译：泛素连接酶COP1是p53的关键负调控因子

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摘要

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.
机译：COP1（构成性光形态发生蛋白1）是一种含有RING指的蛋白质，其功能是抑制植物光形态发生，这是光介导的植物发育程序。 COP1突变体具有组成型的光形态发生作用，这归因于它们无法负面调节蛋白质LAF1（参考文献1）和HY5（参考文献2）。 COP1在哺乳动物细胞中的作用还不太清楚（3）。在这里，我们确定肿瘤抑制蛋白p53为COP1相互作用蛋白。 COP1通过以泛素依赖性方式独立于MDM2或Pirh2（已知与p53相互作用并对其产生负调控）而以蛋白酶体为靶点降解蛋白酶体来增加p53的转化。此外，COP1在体外和体内都充当p53的E3泛素连接酶，并抑制p53依赖性转录和凋亡。短干扰RNA（siRNA）消耗COP1可稳定p53并将细胞停在细胞周期的G1期。此外，我们确定COP1为p53诱导基因，并表明siRNA对COP1和MDM2的耗竭使U2-OS细胞对电离辐射诱导的细胞死亡敏感。总体而言，这些结果表明，COP1是p53的关键负调控因子，代表了在未受压力的细胞中将p53维持在低水平的新途径。

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