Ubiquitination and degradation of mutant p53
Ubiquitination and degradation of mutant p53
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DOI：
10.1128/mcb.00050-07
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发表时间：
2007-12-01
影响因子：
5.3
通讯作者：
Vousden, Karen H.
中科院分区：
文献类型：
--
作者：
Lukashchuk, Natalia;Vousden, Karen H.
虽然野生型 p53 通常是一种快速降解的蛋白质，但 p53 的突变形式在肿瘤细胞中稳定并积累到高水平。在这项研究中，我们发现突变型和野生型 p53 蛋白通过重叠但不同的途径被泛素化和降解。虽然 Mdm2 可以驱动突变型和野生型 p53 的降解，但我们的数据表明，Mdm2 作为泛素连接酶的能力在突变型 p53 的降解中不太重要，突变型 p53 以不依赖 Mdm2 的方式严重泛素化。我们最初尝试鉴定负责突变体 p53 泛素化的泛素连接酶，结果表明分子伴侣相关泛素连接酶 CHIP（Hsc70 相互作用蛋白的 C 末端）发挥作用，尽管其他未鉴定的泛素连接酶似乎也有贡献。 Mdm2 对突变体 p53 降解的贡献可能反映了 Mdm2 将泛素化突变体 p53 递送至蛋白酶体的能力。
While wild-type p53 is normally a rapidly degraded protein, mutant forms of p53 are stabilized and accumulate to high levels in tumor cells. In this study, we show that mutant and wild-type p53 proteins are ubiquitinated and degraded through overlapping but distinct pathways. While Mdm2 can drive the degradation of both mutant and wild-type p53, our data suggest that the ability of Mdm2 to function as a ubiquitin ligase is less important in the degradation of mutant p53, which is heavily ubiquitinated in an Mdm2-independent manner. Our initial attempts to identify ubiquitin ligases that are responsible for the ubiquitination of mutant p53 have suggested a role for the chaperone-associated ubiquitin ligase CHIP (C terminus of Hsc70-interacting protein), although other unidentified ubiquitin ligases also appear to contribute. The contribution of Mdm2 to the degradation of mutant p53 may reflect the ability of Mdm2 to deliver the ubiquitinated mutant p53 to the proteasome.