Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.
Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.
Commun Biol. 2021 Dec 8;4(1):1373. doi: 10.1038/s42003-021-02880-x.
Tumor suppressor p53, a critical regulator of cell fate, is frequently mutated in cancer. Mutation of p53 abolishes its tumor-suppressing functions or endows oncogenic functions. We recently found that p53 binds via its proline-rich domain to peptidase D (PEPD) and is activated when the binding is disrupted. The proline-rich domain in p53 is rarely mutated. Here, we show that oncogenic p53 mutants closely resemble p53 in PEPD binding but are transformed into tumor suppressors, rather than activated as oncoproteins, when their binding to PEPD is disrupted by PEPD knockdown. Once freed from PEPD, p53 mutants undergo multiple posttranslational modifications, especially lysine 373 acetylation, which cause them to refold and regain tumor suppressor activities that are typically displayed by p53. The reactivated p53 mutants strongly inhibit cancer cell growth in vitro and in vivo. Our study identifies a cellular mechanism for reactivation of the tumor suppressor functions of oncogenic p53 mutants.
抑癌基因 p53 是细胞命运的关键调节因子，其在癌症中经常发生突变。p53 的突变会使其抑癌功能丧失或赋予致癌功能。我们最近发现，p53 通过其富含脯氨酸的结构域与肽酶 D（PEPD）结合，当结合被破坏时，p53 被激活。p53 中的富含脯氨酸的结构域很少发生突变。在这里，我们发现致癌性 p53 突变体与 p53 在 PEPD 结合方面非常相似，但当它们与 PEPD 的结合被 PEPD 敲低破坏时，这些突变体被转化为肿瘤抑制因子，而不是被激活为癌蛋白。一旦从 PEPD 中释放出来，p53 突变体就会经历多种翻译后修饰，特别是赖氨酸 373 乙酰化，这导致它们重新折叠并恢复通常由 p53 表现出的肿瘤抑制活性。重新激活的 p53 突变体在体外和体内强烈抑制癌细胞的生长。我们的研究确定了一种细胞机制，可使致癌性 p53 突变体的肿瘤抑制功能重新激活。
