Mechanistic insight into a novel TIF-IA-NF-kB nucleolar stress response pathway and elucidation of its role in senescence

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This proposal focuses on a structure inside the cell called the nucleolus. This structure is dysfunctional in many common disease, including Alzheimer's, Parkinsons disease and cancer. It is also known to play a role in aging. If the environment of a cell changes, for example if nutrients are decreased or the cell is exposed to toxic agents, nucleoli respond and send signals to other parts of the cell to change the rate of growth/death and many other cellular processes. However, how nucleoli sense changes in the environment, and the signals they send to the other parts of the cell, remain poorly understood. We have recently published a new method by which nucleoli respond to stress that involves degradation of a critical nucleolar protein called TIF-IA. We have also demonstrated that this degradation causes an increase in nucleolar size and simulates a protein in another part of the cell called NF-kB. Since increased nucleolar size and NF-kB stimulation are connected with ageing, we looked to see if TIF-IA-NF-kB may be important in this process using a model called oncogene-induced senescence (OIS). Here we aim to gain full understanding of how stresses degrade TIF-IA. We have exciting preliminary data to suggest that this degradation occurs by a novel mechanisms and so, this will be the focus of these studies. We also aim to identify the signals that link changed levels of TIF-IA to altered nucleolar size and NF-kB stimulation. Again we have preliminary data that has revealed some candidates that may be involved in this process. Finally, and importantly, we aim to confirm the role of TIF-IA-NF-kB in senescence. Given that nucleolar dysfunction and NF-kB pathway activation are both markers of ageing and contribute to poor health, these studies have the very real potential of increasing our understanding of this process and identifying biomarkers that could be used to identify diseased or ageing cells. They may also open up avenues for a new class of drugs that act by targeting both these pathways simultaneously.