Abstract

p53 is a key tumor suppressor, and loss of p53 function is frequently a prerequisite for cancer development. The p53 gene is the most frequently mutated gene in human cancers; p53 mutations occur in >50% of all human cancers and in almost every type of human cancers. Most of p53 mutations in cancers are missense mutations, which produce the full-length mutant p53 (mutp53) protein with only one amino acid difference from wild-type p53 protein. In addition to loss of the tumor-suppressive function of wild-type p53, many mutp53 proteins acquire new oncogenic activities independently of wild-type p53 to promote cancer progression, termed gain-of-function (GOF). Mutp53 protein often accumulates to very high levels in cancer cells, which is critical for its GOF. Given the high mutation frequency of the p53 gene and the GOF activities of mutp53 in cancer, therapies targeting mutp53 have attracted great interest. Further understanding the mechanisms underlying mutp53 protein accumulation and GOF will help develop effective therapies treating human cancers containing mutp53. In this review, we summarize the recent advances in the studies on mutp53 regulation and GOF as well as therapies targeting mutp53 in human cancers.

中文翻译：

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癌症进展和治疗中的功能获得性突变 p53。

摘要

p53 是一种关键的肿瘤抑制因子，p53 功能的丧失通常是癌症发展的先决条件。p53 基因是人类癌症中最常见的突变基因。p53 突变发生在超过 50% 的人类癌症和几乎所有类型的人类癌症中。癌症中的大多数 p53 突变是错义突变，它产生全长突变 p53 (mutp53) 蛋白，与野生型 p53 蛋白只有一个氨基酸差异。除了野生型 p53 的肿瘤抑制功能丧失之外，许多 mutp53 蛋白获得了独立于野生型 p53 的新致癌活性以促进癌症进展，称为功能获得 (GOF)。Mutp53 蛋白通常在癌细胞中积累到非常高的水平，这对其 GOF 至关重要。鉴于 p53 基因的高突变频率和 mutp53 在癌症中的 GOF 活性，针对 mutp53 的疗法引起了极大的兴趣。进一步了解 mutp53 蛋白积累和 GOF 的潜在机制将有助于开发治疗含有 mutp53 的人类癌症的有效疗法。在这篇综述中，我们总结了 mutp53 调控和 GOF 研究的最新进展，以及针对人类癌症中 mutp53 的疗法。