Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
Nat Med. 2018 Jul;24(7):947-953. doi: 10.1038/s41591-018-0043-5. Epub 2018 Jun 11.
It has long been assumed that p53 suppresses tumor development through induction of apoptosis, possibly with contributions by cell cycle arrest and cell senescence. However, combined deficiency in these three processes does not result in spontaneous tumor formation as observed upon loss of p53, suggesting the existence of additional mechanisms that are critical mediators of p53-dependent tumor suppression function. To define such mechanisms, we performed in vivo shRNA screens targeting p53-regulated genes in sensitized genetic backgrounds. We found that knockdown of Zmat3, Ctsf and Cav1, promoted lymphoma/leukemia development only when PUMA and p21, the critical effectors of p53-driven apoptosis, cell cycle arrest and senescence, were also absent. Notably, loss of the DNA repair gene Mlh1 caused lymphoma in a wild-type background, and its enforced expression was able to delay tumor development driven by loss of p53. Further examination of direct p53 target genes implicated in DNA repair showed that knockdown of Mlh1, Msh2, Rnf144b, Cav1 and Ddit4 accelerated MYC-driven lymphoma development to a similar extent as knockdown of p53. Collectively, these findings demonstrate that extensive functional overlap of several p53-regulated processes safeguards against cancer and that coordination of DNA repair appears to be an important process by which p53 suppresses tumor development.
长期以来，人们一直认为 p53 通过诱导细胞凋亡来抑制肿瘤的发展，可能还通过细胞周期停滞和细胞衰老来实现。然而，在 p53 缺失的情况下，这三种过程的联合缺失并不会导致自发性肿瘤形成，这表明存在其他额外的机制，这些机制是 p53 依赖性肿瘤抑制功能的关键介质。为了定义这些机制，我们在敏感的遗传背景下针对 p53 调节的基因进行了体内 shRNA 筛选。我们发现，只有在 PUMA 和 p21（p53 驱动的细胞凋亡、细胞周期停滞和衰老的关键效应物）也不存在的情况下，Zmat3、Ctsf 和 Cav1 的敲低才会促进淋巴瘤/白血病的发展。值得注意的是，DNA 修复基因 Mlh1 的缺失会导致野生型背景下的淋巴瘤，而其强制表达能够延缓由 p53 缺失驱动的肿瘤发展。对直接参与 DNA 修复的 p53 靶基因的进一步研究表明，Mlh1、Msh2、Rnf144b、Cav1 和 Ddit4 的敲低与 p53 的敲低一样，能以相似的程度加速 MYC 驱动的淋巴瘤发展。总之，这些发现表明，几种 p53 调节过程的广泛功能重叠可以预防癌症，并且 DNA 修复的协调似乎是 p53 抑制肿瘤发展的一个重要过程。
