Guimaraes D P, Hainaut P
Group of Molecular Carcinogenesis, International Agency for Research on Cancer, Lyon, France.
Biochimie. 2002 Jan;84(1):83-93. doi: 10.1016/s0300-9084(01)01356-6.
TP53 is mutated in most types of human cancers and is one of the most popular genes in cancer research. The p53 protein is a sensor of multiple forms of genotoxic, oncogenic and non-genotoxic stress. It suppresses growth and controls survival of stressed cells, and as such, is the focal point of selection pressures in tissues exposed to carcinogens or to oncogenic changes. Thus, the clonal expansion of cells with mutations in TP53 may be seen as the result of a selection process intrinsic to the natural history of cancer. In this review, we discuss the nature of these various forms of selection pressure. We present a hypothesis to explain why TP53 is often mutated as either an early or a late event in cancer. Furthermore, we also summarise current knowledge on the molecular consequences of mutation for loss of wild-type protein function, dominant-negative activity, and a possible gain of oncogenic function.
TP53在大多数人类癌症类型中发生突变，是癌症研究中最受关注的基因之一。p53蛋白是多种基因毒性、致癌性和非基因毒性应激的感受器。它抑制应激细胞的生长并控制其存活，因此，在暴露于致癌物或发生致癌性改变的组织中，它是选择压力的焦点。因此，TP53发生突变的细胞的克隆性扩增可被视为癌症自然史内在选择过程的结果。在本综述中，我们讨论了这些各种形式选择压力的性质。我们提出一个假说，以解释为什么TP53在癌症中常常作为早期或晚期事件发生突变。此外，我们还总结了目前关于突变对野生型蛋白功能丧失、显性负性活性以及可能获得致癌功能的分子后果的认识。
