Croessmann Sarah, Wong Hong Yuen, Zabransky Daniel J, Chu David, Mendonca Janet, Sharma Anup, Mohseni Morassa, Rosen D Marc, Scharpf Robert B, Cidado Justin, Cochran Rory L, Parsons Heather A, Dalton W Brian, Erlanger Bracha, Button Berry, Cravero Karen, Kyker-Snowman Kelly, Beaver Julia A, Kachhap Sushant, Hurley Paula J, Lauring Josh, Park Ben Ho
The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;
The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; Department of Chemical and Biomolecular Engineering, The Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21218
Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):11583-8. doi: 10.1073/pnas.1503683112. Epub 2015 Aug 31.
The tumor protein 53 (TP53) tumor suppressor gene is the most frequently somatically altered gene in human cancers. Here we show expression of N-Myc down-regulated gene 1 (NDRG1) is induced by p53 during physiologic low proliferative states, and mediates centrosome homeostasis, thus maintaining genome stability. When placed in physiologic low-proliferating conditions, human TP53 null cells fail to increase expression of NDRG1 compared with isogenic wild-type controls and TP53 R248W knockin cells. Overexpression and RNA interference studies demonstrate that NDRG1 regulates centrosome number and amplification. Mechanistically, NDRG1 physically associates with γ-tubulin, a key component of the centrosome, with reduced association in p53 null cells. Strikingly, TP53 homozygous loss was mutually exclusive of NDRG1 overexpression in over 96% of human cancers, supporting the broad applicability of these results. Our study elucidates a mechanism of how TP53 loss leads to abnormal centrosome numbers and genomic instability mediated by NDRG1.
肿瘤蛋白53（TP53）肿瘤抑制基因是人类癌症中最常发生体细胞改变的基因。在此我们表明，在生理低增殖状态下，N - myc下调基因1（NDRG1）的表达由p53诱导，并介导中心体稳态，从而维持基因组稳定性。当置于生理低增殖条件下时，与同基因野生型对照和TP53 R248W敲入细胞相比，人TP53缺失细胞无法增加NDRG1的表达。过表达和RNA干扰研究表明，NDRG1调节中心体数量和扩增。从机制上讲，NDRG1与中心体的关键成分γ - 微管蛋白物理结合，在p53缺失细胞中的结合减少。引人注目的是，在超过96%的人类癌症中，TP53纯合缺失与NDRG1过表达相互排斥，这支持了这些结果的广泛适用性。我们的研究阐明了TP53缺失如何导致由NDRG1介导的中心体数量异常和基因组不稳定的机制。
