Attardi Laura D
Stanford University School of Medicine, Departments of Radiation Oncology and Genetics, CCSR South, Room 1255, 269 Campus Drive, Stanford, CA 94305-5152, USA.
Mutat Res. 2005 Jan 6;569(1-2):145-57. doi: 10.1016/j.mrfmmm.2004.04.019.
Genomic instability is a major force driving human cancer development. A cellular safeguard against such genetic destabilization, which can ensue from defects in telomere maintenance, DNA repair, and checkpoint function, is activation of the p53 tumor suppressor protein, which commonly responds to these DNA damage signals by inducing apoptosis. If, however, p53 becomes inactivated, as is typical of many tumors and pre-cancerous lesions, then cells with compromised genome integrity pathways survive inappropriately, and the accrual of oncogenic lesions can fuel the carcinogenic process. Studies of mouse models have been instrumental in providing support for this idea. Mouse knockouts in genes important for telomere function, DNA damage checkpoint activation and DNA repair - both non-homologous end joining and homologous recombination - are prone to the development of genomic instability. As a consequence of these DNA damage signals, p53 becomes activated in cells of these mutant mice, leading to the induction of apoptosis, sometimes at the expense of organismal viability. This apoptotic response can be rescued through crosses to p53-deficient mice, but has dire consequences: mice predisposed to genomic instability and lacking p53 are susceptible to tumorigenesis. Thus p53-mediated apoptosis provides a crucial tumor suppressive mechanism to eliminate cells succumbing to genomic instability.
基因组不稳定是推动人类癌症发展的主要力量。细胞针对这种可能由端粒维持、DNA修复和检查点功能缺陷引发的基因不稳定的一种保护机制,是激活p53肿瘤抑制蛋白,该蛋白通常通过诱导细胞凋亡来响应这些DNA损伤信号。然而,如果p53失活,这在许多肿瘤和癌前病变中很常见,那么基因组完整性途径受损的细胞就会不恰当地存活下来,致癌性病变的累积会推动致癌过程。对小鼠模型的研究为这一观点提供了支持。敲除对端粒功能、DNA损伤检查点激活以及DNA修复(包括非同源末端连接和同源重组)重要的基因的小鼠,容易发生基因组不稳定。由于这些DNA损伤信号,p53在这些突变小鼠的细胞中被激活,导致细胞凋亡的诱导,有时甚至以机体活力为代价。这种凋亡反应可以通过与p53缺陷小鼠杂交来挽救,但会产生可怕的后果:易发生基因组不稳定且缺乏p53的小鼠易患肿瘤。因此,p53介导的细胞凋亡提供了一种关键的肿瘤抑制机制,以消除因基因组不稳定而死亡的细胞。