An IKKα-Nucleophosmin Axis Utilizes Inflammatory Signaling to Promote Genome Integrity

• Inflammation-associated IKKα activation promotes genomic integrity
• IKKα prevents centrosome amplification by phosphorylating Ser125-NPM
• NPM phosphorylation by IKKα enhances the association of NPM and centrosomes
• Downregulation of IKKα and NPM is found in human squamous cell carcinomas

SummaryThe 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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