An IKKα-Nucleophosmin Axis Utilizes Inflammatory Signaling to Promote Genome Integrity
The inflammatory microenvironment promotes skin tumorigenesis. However, the mechanisms by which cells protect themselves from inflammatory signals are unknown. Downregulation of IKKα promotes skin tumor progression from papillomas to squamous cell carcinomas, which is frequently accompanied by geno...
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doaj-82c7880764134d168b07a3bf8eeda2932020-11-25T01:11:33ZengElsevierCell Reports2211-12472013-12-01551243125510.1016/j.celrep.2013.10.046An IKKα-Nucleophosmin Axis Utilizes Inflammatory Signaling to Promote Genome IntegrityXiaojun Xia0Shuang Liu1Zuoxiang Xiao2Feng Zhu3Na-Young Song4Ming Zhou5Bigang Liu6Jianjun Shen7Kunio Nagashima8Timothy D. Veenstra9Sandra Burkett10Mahesh Datla11Jami Willette-Brown12Haifa Shen13Yinling Hu14Department of Nanomedicine, Houston Methodist Hospital Research Institute, Houston, TX 77030, USACancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USACancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USACancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USACancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USALaboratory of Proteomics and Analytical Technologies, SAIC-Frederick, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USADepartment of Molecular Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Unit 389, Smithville, TX 78957, USADepartment of Molecular Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Unit 389, Smithville, TX 78957, USAAdvanced Technology Program, Electron Microscopy Laboratory, SAIC-Frederick, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USALaboratory of Proteomics and Analytical Technologies, SAIC-Frederick, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USAMouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USACancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USACancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USADepartment of Nanomedicine, Houston Methodist Hospital Research Institute, Houston, TX 77030, USACancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA The inflammatory microenvironment promotes skin tumorigenesis. However, the mechanisms by which cells protect themselves from inflammatory signals are unknown. Downregulation of IKKα promotes skin tumor progression from papillomas to squamous cell carcinomas, which is frequently accompanied by genomic instability, including aneuploid chromosomes and extra centrosomes. In this study, we found that IKKα promoted oligomerization of nucleophosmin (NPM), a negative centrosome duplication regulator, which further enhanced NPM and centrosome association, inhibited centrosome amplification, and maintained genome integrity. Levels of NPM hexamers and IKKα were conversely associated with skin tumor progression. Importantly, proinflammatory cytokine-induced IKKα activation promoted the formation of NPM oligomers and reduced centrosome numbers in mouse and human cells, whereas kinase-dead IKKα blocked this connection. Therefore, our findings suggest a mechanism in which an IKKα-NPM axis may use inflammatory signals to suppress centrosome amplification, promote genomic integrity, and prevent tumor progression. http://www.sciencedirect.com/science/article/pii/S2211124713006451 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xiaojun Xia Shuang Liu Zuoxiang Xiao Feng Zhu Na-Young Song Ming Zhou Bigang Liu Jianjun Shen Kunio Nagashima Timothy D. Veenstra Sandra Burkett Mahesh Datla Jami Willette-Brown Haifa Shen Yinling Hu |
spellingShingle |
Xiaojun Xia Shuang Liu Zuoxiang Xiao Feng Zhu Na-Young Song Ming Zhou Bigang Liu Jianjun Shen Kunio Nagashima Timothy D. Veenstra Sandra Burkett Mahesh Datla Jami Willette-Brown Haifa Shen Yinling Hu An IKKα-Nucleophosmin Axis Utilizes Inflammatory Signaling to Promote Genome Integrity Cell Reports |
author_facet |
Xiaojun Xia Shuang Liu Zuoxiang Xiao Feng Zhu Na-Young Song Ming Zhou Bigang Liu Jianjun Shen Kunio Nagashima Timothy D. Veenstra Sandra Burkett Mahesh Datla Jami Willette-Brown Haifa Shen Yinling Hu |
author_sort |
Xiaojun Xia |
title |
An IKKα-Nucleophosmin Axis Utilizes Inflammatory Signaling to Promote Genome Integrity |
title_short |
An IKKα-Nucleophosmin Axis Utilizes Inflammatory Signaling to Promote Genome Integrity |
title_full |
An IKKα-Nucleophosmin Axis Utilizes Inflammatory Signaling to Promote Genome Integrity |
title_fullStr |
An IKKα-Nucleophosmin Axis Utilizes Inflammatory Signaling to Promote Genome Integrity |
title_full_unstemmed |
An IKKα-Nucleophosmin Axis Utilizes Inflammatory Signaling to Promote Genome Integrity |
title_sort |
ikkα-nucleophosmin axis utilizes inflammatory signaling to promote genome integrity |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2013-12-01 |
description |
The inflammatory microenvironment promotes skin tumorigenesis. However, the mechanisms by which cells protect themselves from inflammatory signals are unknown. Downregulation of IKKα promotes skin tumor progression from papillomas to squamous cell carcinomas, which is frequently accompanied by genomic instability, including aneuploid chromosomes and extra centrosomes. In this study, we found that IKKα promoted oligomerization of nucleophosmin (NPM), a negative centrosome duplication regulator, which further enhanced NPM and centrosome association, inhibited centrosome amplification, and maintained genome integrity. Levels of NPM hexamers and IKKα were conversely associated with skin tumor progression. Importantly, proinflammatory cytokine-induced IKKα activation promoted the formation of NPM oligomers and reduced centrosome numbers in mouse and human cells, whereas kinase-dead IKKα blocked this connection. Therefore, our findings suggest a mechanism in which an IKKα-NPM axis may use inflammatory signals to suppress centrosome amplification, promote genomic integrity, and prevent tumor progression.
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url |
http://www.sciencedirect.com/science/article/pii/S2211124713006451 |
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