NDRG1 links p53 with proliferation-mediated centrosome homeostasis and genome stability
NDRG1 links p53 with proliferation-mediated centrosome homeostasis and genome stability
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DOI：
10.1073/pnas.1503683112
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发表时间：
2015-09-15
影响因子：
11.1
通讯作者：
Park, Ben Ho
中科院分区：
文献类型：
--
作者：
Croessmann, Sarah;Wong, Hong Yuen;Park, Ben Ho
肿瘤蛋白53（TP 53）抑癌基因是人类肿瘤中最常见的体细胞改变基因。在这里，我们显示N-Myc下调基因1（NDRG 1）的表达诱导p53在生理低增殖状态，并介导中心体稳态，从而维持基因组的稳定性。当置于生理低增殖条件下时，与同基因野生型对照和TP 53 R248 W敲入细胞相比，人TP 53空细胞不能增加NDRG 1的表达。过表达和RNA干扰研究表明，NDRG 1调节中心体的数量和扩增。NDRG 1在物理上与。微管蛋白是中心体的关键成分，在p53无效细胞中具有减少的关联。引人注目的是，在超过96%的人类癌症中，TP 53纯合丢失与NDRG 1过表达相互排斥，支持这些结果的广泛适用性。我们的研究阐明了TP 53缺失如何导致NDRG 1介导的异常中心体数目和基因组不稳定性的机制。
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.-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.