期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：37
页码：11583-11588
DOI：10.1073/pnas.1503683112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe mechanism of how loss of the tumor suppressor p53 can lead to genomic instability is not fully understood. This study demonstrates that under physiologic low levels of proliferation, homozygous loss of tumor protein 53 (TP53) via genome editing, but not common p53 missense mutations, results in an inability to increase expression of N-Myc down-regulated gene 1 (NDRG1). In turn, failure to upregulate NDRG1 protein under low proliferative states leads to supernumerary centrosome formation, a known mechanism of aneuploidy. These results provide a mechanistic link between loss of TP53, proliferation, NDRG1, and genomic instability and help explain how cells with a low proliferative index and p53 loss can acquire additional genetic alterations that lead to cancer. 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 {gamma}-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.
