A novel mutant p53 binding partner BAG5 stabilizes mutant p53 and promotes mutant p53 GOFs in tumorigenesis.
A novel mutant p53 binding partner BAG5 stabilizes mutant p53 and promotes mutant p53 GOFs in tumorigenesis.
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DOI：
10.1038/celldisc.2016.39
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发表时间：
2016
期刊：
影响因子：
33.5
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中科院分区：
文献类型：
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肿瘤抑制基因p53是人类肿瘤中最常见的突变基因。许多肿瘤相关的突变型p53 （mutp53）蛋白获得了新的肿瘤促进活性，包括肿瘤细胞增殖、转移和化疗耐药的增加，这被定义为功能获得（GOFs）。Mutp53蛋白在人类肿瘤中经常高水平积累，这对于Mutp53发挥其gof非常重要。mutp53蛋白在肿瘤中积累的机制尚不完全清楚。在这里，我们报道了BAG5， bcl -2相关的无thanogene （BAG）家族蛋白的成员，促进mutp53在肿瘤中的积累，进而增强mutp53的GOFs。在机制上，BAG5与mutp53蛋白相互作用，保护mutp53免受E3泛素连接酶MDM2和CHIP的泛素化和降解，进而促进mutp53蛋白积累，从而促进GOFs促进细胞增殖、肿瘤生长、细胞迁移和化疗耐药。BAG5在许多人类肿瘤中经常过表达，并且BAG5的过表达与癌症患者预后不良有关。总之，本研究揭示了BAG5抑制mutp53降解是癌症中mutp53蛋白积累和GOFs的一个新的关键机制。此外，我们的研究结果还揭示了促进mutp53积累和GOFs是BAG5在肿瘤发生中的新机制。
Tumor suppressor p53 is the most frequently mutated gene in human tumors. Many tumor-associated mutant p53 (mutp53) proteins gain new tumor-promoting activities, including increased proliferation, metastasis and chemoresistance of tumor cells, which are defined as gain-of-functions (GOFs). Mutp53 proteins often accumulate at high levels in human tumors, which is important for mutp53 to exert their GOFs. The mechanism underlying mutp53 proteins accumulation in tumors is not fully understood. Here, we report that BAG5, a member of Bcl-2-associated athanogene (BAG) family proteins, promotes mutp53 accumulation in tumors, which in turn enhances mutp53 GOFs. Mechanistically, BAG5 interacts with mutp53 proteins to protect mutp53 from ubiquitination and degradation by E3 ubiquitin ligases MDM2 and CHIP, which in turn promotes mutp53 protein accumulation and therefore GOFs in promoting cell proliferation, tumor growth, cell migration and chemoresistance. BAG5 is frequently overexpressed in many human tumors and the overexpression of BAG5 is associated with poor prognosis of cancer patients. Altogether, this study revealed that inhibition of mutp53 degradation by BAG5 is a novel and critical mechanism underlying mutp53 protein accumulation and GOFs in cancer. Furthermore, our results also uncovered that promoting mutp53 accumulation and GOFs is a novel mechanism of BAG5 in tumorigenesis.