Identification of a novel TIF-IA-NF-κB nucleolar stress response pathway.
NUCLEIC ACIDS RESEARCH(2018)
摘要
p53 as an effector of nucleolar stress is well defined, but p53 independent mechanisms are largely unknown. Like p53, the NF-kappa B transcription factor plays a critical role in maintaining cellular homeostasis under stress. Many stresses that stimulate NF-kappa B also disrupt nucleoli. However, the link between nucleolar function and activation of the NF-kappa B pathway is as yet unknown. Here we demonstrate that artificial disruption of the PoII complex stimulates NF kappa B 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-kappa B induce degradation of a critical component of the PolI complex, TIF-IA. This degradation precedes activation of NF-kappa B 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-kappa B signalling. Finally, using ex vivo culture, we show a strong correlation between degradation of TIF-IA and activation of NF-kappa B in freshly resected, human colorectal tumours exposed to the chemopreventative agent, aspirin. Together, our study provides compelling evidence for a new, TIF-IA-NF-kappa B nucleolar stress response pathway that has in vivo relevance and therapeutic implications.
更多查看译文
关键词
nucleolar stress response,stress response
AI 理解论文
溯源树
样例
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要