Liu Yunshan, Cao Beibei, Hu Liqiao, Ye Jingjing, Tian Wei, He Xiaojing
Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
Front Cell Dev Biol. 2022 Jul 19;10:922675. doi: 10.3389/fcell.2022.922675. eCollection 2022.
The tumor suppressor p53 is critical for the maintenance of genome stability and protection against tumor malignant transformation, and its homeostasis is usually regulated by ubiquitination. MDM2 is a major E3 ligase of p53 ubiquitination, and its activity is enhanced by TRIM28. TRIM28 also independently ubiquitinates p53 as an E3 ligase activated by MAGE-C2. Moreover, MAGE-C2 is highly expressed in various cancers, but the detailed mechanisms of MAGE-C2 involved in MDM2/TRIM28-mediated p53 ubiquitination remain unknown. Here, we found that MAGE-C2 directly interacts with MDM2 through its conserved MHD domain to inhibit the activity of MDM2 on p53 ubiquitination. Furthermore, TRIM28 acts as an MAGE-C2 binding partner and directly competes with MAGE-C2 for MDM2 interaction, thus releasing the inhibitory role of MAGE-C2 and promoting p53 ubiquitination. MAGE-C2 suppresses cell proliferation in TRIM28-deficient cells, but the overexpression of TRIM28 antagonizes the inhibitory role of MAGE-C2 and accumulates p53 ubiquitination to promote cell proliferation. This study clarified the molecular link of MAGE-C2 in two major E3 systems MDM2 and TRIM28 on p53 ubiquitination. Our results revealed the molecular function of how MAGE-C2 and TRIM28 contribute to p53 ubiquitination and cell proliferation, in which MAGE-C2 acts as a potential inhibitor of MDM2 and TRIM28 is a vital regulator for MAGE-C2 function in p53 protein level and cell proliferation. This work would be helpful to understand the regulation mechanism of tumor suppressor p53.
肿瘤抑制因子p53对于维持基因组稳定性和防止肿瘤恶性转化至关重要，其稳态通常由泛素化调节。MDM2是p53泛素化的主要E3连接酶，TRIM28可增强其活性。TRIM28还作为由MAGE-C2激活的E3连接酶独立地使p53泛素化。此外，MAGE-C2在多种癌症中高表达，但MAGE-C2参与MDM2/TRIM28介导的p53泛素化的详细机制仍不清楚。在此，我们发现MAGE-C2通过其保守的MHD结构域直接与MDM2相互作用，以抑制MDM2对p53泛素化的活性。此外，TRIM28作为MAGE-C2的结合伴侣，直接与MAGE-C2竞争MDM2相互作用，从而释放MAGE-C2的抑制作用并促进p53泛素化。MAGE-C2在TRIM28缺陷型细胞中抑制细胞增殖，但TRIM28的过表达拮抗MAGE-C2的抑制作用并积累p53泛素化以促进细胞增殖。本研究阐明了MAGE-C2在MDM2和TRIM28这两个主要E3系统中对p53泛素化的分子联系。我们的结果揭示了MAGE-C2和TRIM28如何促进p53泛素化和细胞增殖的分子功能，其中MAGE-C2作为MDM2的潜在抑制剂，而TRIM28是p53蛋白水平和细胞增殖中MAGE-C2功能的重要调节因子。这项工作将有助于理解肿瘤抑制因子p53的调控机制。
