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

ABSTRACT: The inflammatory microenvironment promotes skin tumorigenesis. However, the mechanisms by which cells protect themselves from inflammatory signals are unknown. Downregulation of IKK? 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 IKK? 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 IKK? were conversely associated with skin tumor progression. Importantly, proinflammatory cytokine-induced IKK? activation promoted the formation of NPM oligomers and reduced centrosome numbers in mouse and human cells, whereas kinase-dead IKK? blocked this connection. Therefore, our findings suggest a mechanism in which an IKK?-NPM axis may use inflammatory signals to suppress centrosome amplification, promote genomic integrity, and prevent tumor progression.

SUBMITTER: Xia X

PROVIDER: S-EPMC4159076 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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

Xia Xiaojun X Liu Shuang S Xiao Zuoxiang Z Zhu Feng F Song Na-Young NY Zhou Ming M Liu Bigang B Shen Jianjun J Nagashima Kunio K Veenstra Timothy D TD Burkett Sandra S Datla Mahesh M Willette-Brown Jami J Shen Haifa H Hu Yinling Y

Cell reports 20131127 5

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, w ...[more]

PMID: 24290756

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Project description:The inhibitor-?B kinase-nuclear factor-?B (IKK-NF-?B) and epidermal growth factor receptor-activator protein-1 (EGFR-AP1) pathways are often co-activated and promote malignant behavior, but the underlying basis for this relationship is unclear. Resistance to inhibitors of IKK? or EGFR is observed in head and neck squamous cell carcinomas (HNSCC). Here, we reveal that both IKK? and ? contribute to nuclear activation of canonical and alternate NF-?B/REL family transcription factors, and overexpression of signal components that enhance co-activation of the EGFR-AP1 pathway. We observed that IKK? and IKK? exhibit increased protein expression, nuclear localization, and phosphorylation in HNSCC tissues and cell lines. Individually, IKK activity varied among different cell lines, but overexpression of both IKKs induced the strongest NF-?B activation. Conversely, siRNA knock down of both IKKs significantly decreased nuclear localization and phosphorylation of canonical RELA and I?B? and alternative p52 and RELB subunits. Knock down of both IKKs more effectively inhibited NF-?B activation, broadly modulated gene expression and suppressed cell proliferation and migration. Global expression profiling revealed that NF-?B, cytokine, inflammatory response and growth factor signaling are among the top pathways and networks regulated by IKKs. Importantly, IKK? and IKK? together promoted the expression and activity of transforming growth factor ?, EGFR and AP1 transcription factors cJun, JunB and Fra1. Knock down of AP1 subunits individually decreased 8/15 (53%) of IKK-targeted genes sampled and similarly inhibited cell proliferation and migration. Mutations of NF-?B and AP1-binding sites abolished or decreased IKK-induced interleukin-8 (IL-8) promoter activity. Compounds such as wedelactone with dual IKK inhibitory activity and geldanomycins that block IKK?/? and EGFR pathways were more active than IKK?-specific inhibitors in suppressing NF-?B activation and proliferation and inducing cell death. We conclude that IKK? and IKK? cooperatively activate NF-?B and EGFR/AP1 networks of signaling pathways and contribute to the malignant phenotype and the intrinsic or acquired therapeutic resistance of HNSCC.

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

Publications

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

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