Nucleolar stress stimulates the NF-kappaB pathway: mechanism underlying the proapoptotic effects of aspirin
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Date
01/12/2017Item status
Restricted AccessEmbargo end date
01/12/2018Author
Chen, Jingyu
Metadata
Abstract
The nucleolus is a multifunctional organelle that, in addition to its primary role in
ribosome biogenesis, has emerged as a critical stress sensor and coordinator of stress
response. However, the molecular nature of how nucleoli sense stress and coordinate
downstream cellular consequence remains poorly understood. NF-κB signalling is a
critical regulator of stress response. Many cellular stresses that disrupt nucleolar
function also stimulate the NF-κB pathway. However, the role of NF-κB as a
downstream effector of nucleolar stress has not yet been examined. Aspirin, a known
chemopreventative agent, stimulates the NF-κB pathway to mediate apoptosis but the
upstream mechanisms are unclear. In this thesis, I identified a novel nucleolar stress
response pathway that culminates in activation of NF-κB signalling, and
demonstrated the significance of this nucleolar pathway in the anti-tumour effects of
aspirin. Using multiple approaches, I made the novel observations that disruption of
the Pol I complex activates the cytoplasmic NF-κB signalling pathway. I show that
multiple stress stimuli of NF-κB pathway induce degradation of the crucial Pol I
complex component, rDNA transcription initiation factor IA (TIF-IA). I identified
the tumour suppressor, p14ARF and the Pol I complex component, upstream binding
factor (UBF) as mediators of this degradation. I revealed that inhibition of CDK4
activity lies upstream of UBF/p14ARF-facilitated TIF-IA degradation. Furthermore,
using different approaches I show that blocking aspirin/CDK4i-mediated degradation
of TIF-IA blocks the effects of these agents on nucleolar morphology and NF-κB
signalling. Finally, I show this nucleolar stress response pathway, containing a
UBF/p14ARF/TIF-IA axis, is utilized by aspirin to kill colon cancer cells. Taken
together, this data presented in this thesis advances understanding of nucleolar stress
response, and has therapeutic implications with regard to the anti-tumour effects of
aspirin.