The ubiquitin ligase TRIM21 regulates mutant p53 accumulation and gain of function in cancer.
The ubiquitin ligase TRIM21 regulates mutant p53 accumulation and gain of function in cancer.
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DOI：
10.1172/jci164354
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发表时间：
2023-03-15
影响因子：
15.9
通讯作者：
Feng, Zhaohui
中科院分区：
文献类型：
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作者：
Liu, Juan;Zhang, Cen;Xu, Dandan;Zhang, Tianliang;Chang, Chun-Yuan;Wang, Jianming;Liu, Jie;Zhang, Lanjing;Haffty, Bruce G.;Zong, Wei-Xing;Hu, Wenwei;Feng, Zhaohui
肿瘤抑制基因TP53是人类癌症中最常见的突变基因。突变型p53（mutp53）蛋白通常在人类癌症中积累到非常高的水平，通过功能获得（GOF）机制促进癌症进展。目前，mutp53积累和GOF的机制还不完全清楚。在这里，我们确定TRIM21作为一个关键的E3泛素连接酶的mutp53通过筛选特定的mutp53相互作用的蛋白。TRIM 21与mutp53直接相互作用，而不与WT p53相互作用，导致mutp53的泛素化和降解，从而抑制肿瘤发生中的mutp53 GOF。TRIM21缺陷促进肿瘤发生中mutp53的积累和GOF。与p53 R172 H基因敲入小鼠相比，p53 R172 H基因敲入小鼠中的TRIM 21缺失导致mutp53在正常组织中积累，肿瘤发病更早，小鼠寿命缩短。此外，TRIM21在一些人类癌症中经常下调，包括结肠直肠癌和乳腺癌，并且TRIM21低表达与携带mutp53的癌症患者的预后不良相关。我们的研究结果揭示了mutp53在癌症中积累的关键机制，也揭示了TRIM 21的重要肿瘤抑制功能及其在携带mutp53的癌症中的机制。
The tumor suppressor TP53 is the most frequently mutated gene in human cancers. Mutant p53 (mutp53) proteins often accumulate to very high levels in human cancers to promote cancer progression through the gain-of-function (GOF) mechanism. Currently, the mechanism underlying mutp53 accumulation and GOF is incompletely understood. Here, we identified TRIM21 as a critical E3 ubiquitin ligase of mutp53 by screening for specific mutp53-interacting proteins. TRIM21 directly interacted with mutp53 but not WT p53, resulting in ubiquitination and degradation of mutp53 to suppress mutp53 GOF in tumorigenesis. TRIM21 deficiency in cancer cells promoted mutp53 accumulation and GOF in tumorigenesis. Compared with p53R172H knockin mice, which displayed mutp53 accumulation specifically in tumors but not normal tissues, TRIM21 deletion in p53R172H knockin mice resulted in mutp53 accumulation in normal tissues, an earlier tumor onset, and a shortened life span of mice. Furthermore, TRIM21 was frequently downregulated in some human cancers, including colorectal and breast cancers, and low TRIM21 expression was associated with poor prognosis in patients with cancers carrying mutp53. Our results revealed a critical mechanism underlying mutp53 accumulation in cancers and also uncovered an important tumor-suppressive function of TRIM21 and its mechanism in cancers carrying mutp53.