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 Beaver; Sushant Kachhap; Paula Hurley; Josh David Lauring; Ben Ho Park

doi:10.1073/pnas.1503683112

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 Beaver, Sushant Kachhap, Paula HurleyJosh David Lauring, Ben Ho Park

School of Medicine

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

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 language	English (US)
Pages (from-to)	11583-11588
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	112
Issue number	37
DOIs	https://doi.org/10.1073/pnas.1503683112
State	Published - Sep 15 2015

Keywords

Centrosomes
Genomic instability
NDRG1
P53
Proliferation

ASJC Scopus subject areas

General

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10.1073/pnas.1503683112

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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., 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

Croessmann, S, Wong, HY, Zabransky, DJ, Chu, D, Mendonca, J, Sharmaa, A, Mohseni, M, Rosen, DM, Scharpf, RB, Cidado, J, Cochran, RL, Parsons, HA, Dalton, WB, Erlanger, B, Button, B, Cravero, K, Kyker-Snowman, K, Beaver, J, Kachhap, S, Hurley, P, Lauring, JD & Park, BH 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, vol. 112, no. 37, pp. 11583-11588. https://doi.org/10.1073/pnas.1503683112

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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.",

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AU - Wong, Hong Yuen

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AU - Chu, David

AU - Mendonca, Janet

AU - Sharmaa, Anup

AU - Mohseni, Morassa

AU - Rosen, D. Marc

AU - Scharpf, Robert B.

AU - Cidado, Justin

AU - Cochran, Rory L.

AU - Parsons, Heather A.

AU - Dalton, W. Brian

AU - Erlanger, Bracha

AU - Button, Berry

AU - Cravero, Karen

AU - Kyker-Snowman, Kelly

AU - Beaver, Julia

AU - Kachhap, Sushant

AU - Hurley, Paula

AU - Lauring, Josh David

AU - Park, Ben Ho

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N2 - 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.

AB - 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.

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

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