The Dual Roles of MAGE-C2 in p53 Ubiquitination and Cell Proliferation Through E3 Ligases MDM2 and TRIM28.
The Dual Roles of MAGE-C2 in p53 Ubiquitination and Cell Proliferation Through E3 Ligases MDM2 and TRIM28.
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DOI：
10.3389/fcell.2022.922675
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发表时间：
2022
影响因子：
5.5
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中科院分区：
文献类型：
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抑癌基因p53在维持基因组稳定性和防止肿瘤恶性转化中起着重要作用，其稳态通常受泛素化的调节。MDM 2是p53泛素化的主要E3连接酶，其活性被TRIM 28增强。TRIM 28还作为由MAGE-C2激活的E3连接酶独立地泛素化p53。此外，MAGE-C2在各种癌症中高度表达，但MAGE-C2参与MDM 2/TRIM 28介导的p53泛素化的详细机制仍然未知。在这里，我们发现MAGE-C2通过其保守的MHD结构域直接与MDM 2相互作用，抑制MDM 2对p53遍在蛋白化的活性。此外，TRIM 28作为MAGE-C2结合伴侣，直接与MAGE-C2竞争MDM 2相互作用，从而释放MAGE-C2的抑制作用并促进p53泛素化。MAGE-C2抑制TRIM 28缺陷细胞中的细胞增殖，但TRIM 28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在两个主要的E3系统MDM 2和TRIM 28中对p53泛素化的分子联系。我们的研究结果揭示了MAGE-C2和TRIM 28如何参与p53泛素化和细胞增殖的分子功能，其中MAGE-C2作为MDM 2的潜在抑制剂，TRIM 28是MAGE-C2在p53蛋白水平和细胞增殖中功能的重要调节剂。本研究为深入了解抑癌基因p53的调控机制提供了理论依据。
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.
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