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Cell Rep. 2013 Dec 12;5(5):1243-55. doi: 10.1016/j.celrep.2013.10.046. Epub 2013 Nov 27.

An IKKα-nucleophosmin axis utilizes inflammatory signaling to promote genome integrity.

Author information

1
Department of Nanomedicine, Houston Methodist Hospital Research Institute, Houston, TX 77030, USA.
2
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA.
3
Laboratory of Proteomics and Analytical Technologies, SAIC-Frederick, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA.
4
Department of Molecular Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Unit 389, Smithville, TX 78957, USA.
5
Advanced Technology Program, Electron Microscopy Laboratory, SAIC-Frederick, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA.
6
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA.
7
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA. Electronic address: huy2@mail.nih.gov.

Abstract

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.

PMID:
24290756
PMCID:
PMC4159076
DOI:
10.1016/j.celrep.2013.10.046
[Indexed for MEDLINE]
Free PMC Article

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