NDRG1 links p53 with proliferation-mediated centrosome homeostasis and genome stability

Sarah Croessmann, Hong Yuen Wong, Daniel J. Zabransky, David Chu, Janet Mendonca, Anup Sharmaa, Morassa Mohseni, D. Marc Rosen, Robert B. Scharpf, Justin Cidado, Rory L. Cochran, Heather A. Parsons, W. Brian Dalton, Bracha Erlanger, Berry Button, Karen Cravero, Kelly Kyker-Snowman, Julia A. Beaver, Sushant Kachhap, Paula J. HurleyJosh Lauring, Ben Ho Park

Research output: Contribution to journalArticle

Abstract

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 amechanism of how TP53 loss leads to abnormal centrosome numbers and genomic instability mediated by NDRG1.

Original languageEnglish (US)
Pages (from-to)11583-11588
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number37
DOIs
StatePublished - Sep 15 2015

Keywords

  • Centrosomes
  • Genomic instability
  • NDRG1
  • P53
  • Proliferation

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'NDRG1 links p53 with proliferation-mediated centrosome homeostasis and genome stability'. Together they form a unique fingerprint.

  • Cite this

    Croessmann, S., Wong, H. Y., Zabransky, D. J., Chu, D., Mendonca, J., Sharmaa, A., Mohseni, M., Rosen, D. M., Scharpf, R. B., Cidado, J., Cochran, R. L., Parsons, H. A., Dalton, W. B., Erlanger, B., Button, B., Cravero, K., Kyker-Snowman, K., Beaver, J. A., Kachhap, S., ... Park, B. H. (2015). NDRG1 links p53 with proliferation-mediated centrosome homeostasis and genome stability. Proceedings of the National Academy of Sciences of the United States of America, 112(37), 11583-11588. https://doi.org/10.1073/pnas.1503683112