It takes a team: a gain-of-function story of p53-R249S
It takes a team: a gain-of-function story of p53-R249S
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DOI：
10.1093/jmcb/mjy086
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发表时间：
2019-01
影响因子：
5.5
通讯作者：
Huai Wang;P. Liao;Shelya X. Zeng;Hua Lu
中科院分区：
文献类型：
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作者：
Huai Wang;P. Liao;Shelya X. Zeng;Hua Lu
摘要 功能获得 (GOF) 是一种促癌蛋白最恶意的致癌活性，它充分说明了 R248、R175 和 R273 处的三个热点 p53 突变具有不同的分子机制。然而，人们对另一个热点 p53 突变体 R249S (p53-R249S) 知之甚少。 p53-R249S 是肝细胞癌 (HCC) 中的唯一热点突变，与慢性乙型肝炎病毒 (HBV) 感染和饮食中黄曲霉毒素 B1 (AFB1) 暴露高度相关。其 GOF 的事实表明，该突变体与 HCC 较早发病和癌症患者较差的预后相关，并且其过度表达会促进 HCC 增殖和肿瘤发生。相比之下，简单地在正常小鼠中敲入该突变体并没有显示出明显的 GOF 活性。因此，p53-R249S 的 GOF 活性及其潜在机制一直难以捉摸，直到最近的发现提供了一些新的见解。本综述将讨论这些发现及其临床意义和对开发靶向多种分子作为 p53-R249S 携带 HCC 治疗策略的影响。
Abstract Gain-of-function (GOF), the most malicious oncogenic activity of a cancer-promoting protein, is well illustrated to three hotspot p53 mutations at R248, R175, and R273 with distinct molecular mechanisms. Yet, less is known about another hotspot p53 mutant, R249S (p53-R249S). p53-R249S is the sole hotspot mutation in hepatocellular carcinoma (HCC) that is highly associated with chronic hepatitis B virus (HBV) infection and dietary exposure to aflatoxin B1 (AFB1). Its GOF is suggested by the facts that this mutant is associated with earlier onset of HCC and poorer prognosis of cancer patients and that its overexpression drives HCC proliferation and tumorigenesis. By contrast, simply knocking in this mutant in normal mice did not show apparent GOF activity. Hence, the GOF activity for p53-R249S and its underlying mechanisms have been elusive until recent findings offered some new insights. This review will discuss these findings as well as their clinical significance and implications for the development of a strategy to target multiple molecules as a therapy for p53-R249S-harboring HCC.