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Identification of a novel TIF-IA-NF-κB nucleolar stress response pathway

Lookup NU author(s): Professor Fiona Oakley

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research. p53 as an effector of nucleolar stress is well defined, but p53 independent mechanisms are largely unknown. Like p53, the NF-κB transcription factor plays a critical role in maintaining cellular homeostasis under stress. Many stresses that stimulate NF-κB also disrupt nucleoli. However, the link between nucleolar function and activation of the NF-κB pathway is as yet unknown. Here we demonstrate that artificial disruption of the PolI complex stimulates NF-κB signalling. Unlike p53 nucleolar stress response, this effect does not appear to be linked to inhibition of rDNA transcription. We show that specific stress stimuli of NF-κB induce degradation of a critical component of the PolI complex, TIF-IA. This degradation precedes activation of NF-κB and is associated with increased nucleolar size. It is mimicked by CDK4 inhibition and is dependent upon a novel pathway involving UBF/p14ARF and S44 of the protein. We show that blocking TIF-IA degradation blocks stress effects on nucleolar size and NF-κB signalling. Finally, using ex vivo culture, we show a strong correlation between degradation of TIF-IA and activation of NF-κB in freshly resected, human colorectal tumours exposed to the chemopreventative agent, aspirin. Together, our study provides compelling evidence for a new, TIF-IA-NF-κB nucleolar stress response pathway that has in vivo relevance and therapeutic implications.


Publication metadata

Author(s): Chen J, Lobb IT, Morin P, Novo SM, Simpson J, Kennerknecht K, Von Kriegsheim A, Batchelor EE, Oakley F, Stark LA

Publication type: Article

Publication status: Published

Journal: Nucleic Acids Research

Year: 2018

Volume: 46

Issue: 12

Pages: 6188-6205

Online publication date: 05/06/2018

Acceptance date: 14/05/2018

ISSN (print): 0305-1048

ISSN (electronic): 1362-4962

Publisher: Oxford University Press

URL: https://doi.org/10.1093/nar/gky455

DOI: 10.1093/nar/gky455


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