Olivier M, Petitjean A, Marcel V, Pétré A, Mounawar M, Plymoth A, de Fromentel C C, Hainaut P
1Group of Molecular Carcinogenesis and Biomarkers, International Agency for Research on Cancer, World Health Organization, Lyon, France.
Cancer Gene Ther. 2009 Jan;16(1):1-12. doi: 10.1038/cgt.2008.69. Epub 2008 Sep 19.
The TP53 gene is one of the most studied genes in human cancer. In recent years, considerable interest was focused on mutant p53, the abnormal protein product of TP53 somatic or germline alleles with missense mutations that often accumulate in cancer cells. There is now compelling experimental evidence that many mutations can exert mutant-specific, gain-of-function effects by perturbing the regulation of expression of multiple genes. This notion is supported by the observation that targeted mutant p53 expression enhances the formation of specific cancers in the mouse even in the absence of wild-type p53 expression. In addition, clinical studies are producing a wealth of functional pathway data demonstrating correlations between specific TP53 mutations and gene expression patterns identified by transcriptome studies. These correlations imply that alteration of p53 function is critical in shaping gene expression patterns in cancer. Finally, progress is being made in the development of new therapeutic approaches targeting p53 alterations. Key advances regarding the structural, biochemical and functional properties of normal and mutant p53 proteins, their abnormal regulation and distribution in human cancers, and their associations with clinical and pathological cancer characteristics are reviewed. New opportunities for translational research for improving cancer detection, prognosis, prevention and therapy based upon the integration of this knowledge are described.
TP53基因是人类癌症研究最多的基因之一。近年来，人们对突变型p53高度关注，它是TP53体细胞或种系等位基因的异常蛋白质产物，错义突变常累积于癌细胞中。现在有令人信服的实验证据表明，许多突变可通过干扰多个基因的表达调控发挥突变特异性的功能获得效应。这一观点得到以下观察结果的支持：即使在没有野生型p53表达的情况下，靶向突变型p53表达也会增强小鼠特定癌症的形成。此外，临床研究正在产生大量功能通路数据，证明特定的TP53突变与转录组研究确定的基因表达模式之间存在相关性。这些相关性意味着p53功能的改变在塑造癌症基因表达模式中至关重要。最后，针对p53改变的新治疗方法的开发正在取得进展。本文综述了正常和突变型p53蛋白的结构、生化和功能特性、它们在人类癌症中的异常调控和分布，以及它们与癌症临床和病理特征的关联。描述了基于这些知识整合来改善癌症检测、预后、预防和治疗的转化研究新机遇。
