E3 ubiquitin ligase TRIM32 negatively regulates tumor suppressor p53 to promote tumorigenesis
E3 ubiquitin ligase TRIM32 negatively regulates tumor suppressor p53 to promote tumorigenesis
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DOI：
10.1038/cdd.2014.121
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发表时间：
2014-11-01
影响因子：
12.4
通讯作者：
Feng, Z.
中科院分区：
文献类型：
--
作者：
Liu, Ju;Zhang, C.;Feng, Z.
肿瘤抑制因子p53通过调控细胞应激反应，包括细胞凋亡、细胞周期阻滞和衰老，在维持基因组稳定性和防止肿瘤发生方面发挥关键作用。为了保证p53在细胞中的正常水平和功能，p53主要通过翻译后修饰（如泛素化）受到严格调控。在这里，我们发现E3泛素连接酶TRIM32是一个新的p53靶基因和p53介导的应激反应的负调节因子。在DNA损伤等应激反应中，p53与TRIM32基因启动子中的p53应答元件结合，通过转录诱导细胞中TRIM32的表达。反过来，TRIM32与p53相互作用并通过泛素化促进p53降解。因此，TRIM32在应激反应中负调控p53介导的细胞凋亡、细胞周期阻滞和衰老。TRIM32在不同类型的人类肿瘤中经常过表达。在小鼠中，TRIM32过表达以p53依赖的方式促进细胞的致癌转化和肿瘤发生。综上所述，我们的研究结果表明，TRIM32作为一种新的p53靶点和p53的新型负调节因子，在p53和p53介导的细胞应激反应的调控中具有重要作用。此外，我们的研究结果还揭示了p53功能受损是TRIM32在肿瘤发生中的新机制。
Tumor suppressor p53 has a key role in maintaining genomic stability and preventing tumorigenesis through its regulation of cellular stress responses, including apoptosis, cell cycle arrest and senescence. To ensure its proper levels and functions in cells, p53 is tightly regulated mainly through post-translational modifications, such as ubiquitination. Here, we identified E3 ubiquitin ligase TRIM32 as a novel p53 target gene and negative regulator to regulate p53-mediated stress responses. In response to stress, such as DNA damage, p53 binds to the p53 responsive element in the promoter of the TRIM32 gene and transcriptionally induces the expression of TRIM32 in cells. In turn, TRIM32 interacts with p53 and promotes p53 degradation through ubiquitination. Thus, TRIM32 negatively regulates p53-mediated apoptosis, cell cycle arrest and senescence in response to stress. TRIM32 is frequently overexpressed in different types of human tumors. TRIM32 overexpression promotes cell oncogenic transformation and tumorigenesis in mice in a largely p53-dependent manner. Taken together, our results demonstrated that as a novel p53 target and a novel negative regulator for p53, TRIM32 has an important role in regulation of p53 and p53-mediated cellular stress responses. Furthermore, our results also revealed that impairing p53 function is a novel mechanism for TRIM32 in tumorigenesis.