Identification of a novel TIF-IA-NF-κB nucleolar stress response pathway
| Autor: | Jingyu, Chen, Ian T, Lobb, Pierre, Morin, Sonia M, Novo, James, Simpson, Kathrin, Kennerknecht, Alex, von Kriegsheim, Emily E, Batchelor, Fiona, Oakley, Lesley A, Stark |
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| Rok vydání: | 2018 |
| Předmět: |
Active Transport
Cell Nucleus NF-kappa B Transcription Factor RelA Cyclin-Dependent Kinase 4 Cell Line RNA Polymerase I Stress Physiological Cell Line Tumor Tumor Suppressor Protein p14ARF Serine Humans Pol1 Transcription Initiation Complex Proteins Molecular Biology Cell Nucleolus Signal Transduction |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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