Mechanistic insight into a novel TIF-IA-NF-kB nucleolar stress response pathway and elucidation of its role in senescence
Award Number
BB/S018530/1Status / Stage
CompletedDates
1 September 2019 -27 January 2023
Duration (calculated)
03 years 04 monthsFunder(s)
BBSRC (UKRI)Funding Amount
£388,099.00Funder/Grant study page
BBSRC UKRIContracted Centre
University of EdinburghPrincipal Investigator
Dr Lesley StarkPI Contact
Lesley.Stark@ed.ac.ukPI ORCID
0000-0002-6260-6521WHO Catergories
Understanding Underlying DiseaseDisease Type
Dementia (Unspecified)CPEC Review Info
| Reference ID | 711 |
|---|---|
| Researcher | Reside Team |
| Published | 07/07/2023 |
Data
| Award Number | BB/S018530/1 |
|---|---|
| Status / Stage | Completed |
| Start Date | 20190901 |
| End Date | 20230127 |
| Duration (calculated) | 03 years 04 months |
| Funder/Grant study page | BBSRC UKRI |
| Contracted Centre | University of Edinburgh |
| Funding Amount | £388,099.00 |
Abstract
The nucleolus is a highly dynamic nuclear organelle which acts as a critical stress sensor and coordinates downstream responses to stress such as metabolism, differentiation, senescence and apoptosis. Perturbations in nucleolar function are associated with many common diseases and nucleolar size and number are emerging as key markers of longevity. Indeed, proper dynamic control of nucleolar activity is crucial for maintaining tissue homeostasis and health. However, understanding of the regulatory networks that control the activity of nucleoli, and those that link altered function to changes in cell physiology, are poorly understood. In this lab, we have recently identified a novel nucleolar stress response pathway which involves degradation of the critical PolI complex component, TIF-IA and subsequently, increased nucleolar size and activation of NF-kB signalling. We have shown this TIF-IA-NF-kB pathway is important in regulating cell growth/death and our preliminary data suggest it also has a role in senescence Here we aim to: 1. Elucidate the mechanisms that regulate stress-mediated degradation of TIF-IA. Our preliminary data suggest for the first time that the protein is degraded in an autophagy dependent manner and so, studies will focus on this mechanism. 2. Identify the signalling networks that link TIF-IA degradation to increased nucleolar size and activation of the NF-kB pathway. 3. Fully establish the role of TIF-IA-NF-kB signalling in senescence. The nucleolar phenotype we observe in response to stress parallels that observed in ageing cells, which also show hyperactive NF-kB. The three complementary aims outlined in this proposal will provide a deep understanding of how environmental changes can alter nucleolar function through TIF-IA, and how nucleoli signal to the NF-kB pathway. This could have significant implications for our understanding of the aetiology of ageing and identify biomarkers of this process and therapeutic targets.
Aims
Here we aim to: 1. Elucidate the mechanisms that regulate stress-mediated degradation of TIF-IA. Our preliminary data suggest for the first time that the protein is degraded in an autophagy dependent manner and so, studies will focus on this mechanism. 2. Identify the signalling networks that link TIF-IA degradation to increased nucleolar size and activation of the NF-kB pathway. 3. Fully establish the role of TIF-IA-NF-kB signalling in senescence.