Efeyan A, Collado M, Velasco-Miguel S, Serrano M
Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain.
Oncogene. 2007 Mar 8;26(11):1645-9. doi: 10.1038/sj.onc.1209972. Epub 2006 Sep 11.
Protein p21Cip1/Waf1 is transcriptionally activated by the tumour suppressor p53 and previous studies have shown that p21 plays a role in tumour suppression. However, the involvement of p21 in p53-mediated tumour suppression remains to be directly demonstrated in vivo. Tumour suppression mediated by p53 can be measured by comparing tumour susceptibility in animals carrying two (wild-type mice) or three (super-p53 mice) copies of the p53 gene. We have taken advantage of this genetically defined system to measure p53-mediated cell-cycle arrest, apoptosis and tumorigenesis, in a p21 wild-type and in a p21-null context. The absence of p21 significantly impaired the enhanced p53-mediated cell-cycle arrest characteristic of super-p53 cells, but did not affect the enhanced apoptosis. Importantly, in an experimental model of fibrosarcoma induction, the absence of p21 significantly decreased the tumour suppression benefit of super-p53 mice. We conclude that cell-cycle arrest through p21 plays a significant role in mediating p53-dependent cancer protection.
蛋白质p21Cip1/Waf1由肿瘤抑制因子p53转录激活，先前的研究表明p21在肿瘤抑制中发挥作用。然而，p21在p53介导的肿瘤抑制中的作用仍有待在体内直接证实。通过比较携带两个（野生型小鼠）或三个（超级p53小鼠）p53基因拷贝的动物的肿瘤易感性，可以测量p53介导的肿瘤抑制作用。我们利用这个遗传定义的系统，在p21野生型和p21缺失的背景下，测量p53介导的细胞周期阻滞、细胞凋亡和肿瘤发生。p21的缺失显著损害了超级p53细胞增强的p53介导的细胞周期阻滞特征，但不影响增强的细胞凋亡。重要的是，在纤维肉瘤诱导的实验模型中，p21的缺失显著降低了超级p53小鼠的肿瘤抑制益处。我们得出结论，通过p21的细胞周期阻滞在介导p53依赖性癌症保护中起重要作用。
