Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Department of Head and Neck Surgery, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, 100142, Beijing, China.
Nat Commun. 2024 Jan 2;15(1):180. doi: 10.1038/s41467-023-44239-2.
Inactivating TP53 mutations leads to a loss of function of p53, but can also often result in oncogenic gain-of-function (GOF) of mutant p53 (mutp53) proteins which promotes tumor development and progression. The GOF activities of TP53 mutations are well documented, but the mechanisms involved remain poorly understood. Here, we study the mutp53 interactome and find that by targeting minichromosome maintenance complex components (MCMs), GOF mutp53 predisposes cells to replication stress and chromosomal instability (CIN), leading to a tumor cell-autonomous and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-dependent cytosolic DNA response that activates downstream non-canonical nuclear factor kappa light chain enhancer of activated B cell (NC-NF-κB) signaling. Consequently, GOF mutp53-MCMs-CIN-cytosolic DNA-cGAS-STING-NC-NF-κB signaling promotes tumor cell metastasis and an immunosuppressive tumor microenvironment through antagonizing interferon signaling and regulating genes associated with pro-tumorigenic inflammation. Our findings have important implications for understanding not only the GOF activities of TP53 mutations but also the genome-guardian role of p53 and its inactivation during tumor development and progression.
TP53 基因突变导致 p53 功能丧失，但也常常导致突变型 p53（mutp53）蛋白的致癌获得性功能（GOF），从而促进肿瘤的发生和发展。TP53 基因突变的 GOF 活性已有充分的文献记载，但相关机制仍知之甚少。在这里，我们研究了 mutp53 互作组，发现通过靶向微小染色体维持复合物成分（MCMs），GOF mutp53 使细胞易发生复制应激和染色体不稳定（CIN），导致肿瘤细胞自主和环鸟苷酸-腺苷酸合成酶（cGAS）-干扰素基因刺激物（STING）依赖性细胞质 DNA 反应，激活下游非经典核因子κB 轻链增强子激活 B 细胞（NC-NF-κB）信号。因此，GOF mutp53-MCMs-CIN-cytosolic DNA-cGAS-STING-NC-NF-κB 信号通过拮抗干扰素信号和调节与促肿瘤炎症相关的基因，促进肿瘤细胞转移和免疫抑制性肿瘤微环境。我们的发现不仅对理解 TP53 基因突变的 GOF 活性，而且对 p53 的基因组保护作用及其在肿瘤发生和发展过程中的失活具有重要意义。
