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ERC

METABOp53 Report Summary

Project ID: 322842
Funded under: FP7-IDEAS-ERC
Country: United Kingdom

Final Report Summary - METABOP53 (Metabolic functions of p53 in non-cancer pathologies)

The p53 protein plays an important role in tumour suppression, with almost all cancers showing loss of normal p53 function. p53 helps cells detect and respond to stress, and our work has shown that there can be diverse outcomes to p53 activation. Under conditions of extreme or persistent stress, for example when cancer genes are activated, p53 eliminates the affected cell and so prevents cancer development. This activity of p53 can also contribute to neurodegenerative diseases and premature aging. One of the key outcomes of our work was to show that p53 can also function to help cell survival and adaptation under conditions of metabolic stress. We showed that p53 supports the ability of cells to adapt to nutrient starvation, focusing on the mechanisms that allow adaptation to deprivation of non-essential amino acids. We identified a number of p53-induced proteins that allow the mobilisation of endogenous pathways for amino acid synthesis when cells are starved of an external source of serine or glutamine. Activation of the expression of proteins such as the cell cycle inhibitor p21 and the amino acid transporter Slc1a3 help cells to make the switch to de novo serine or glutamine synthesis, and so protect cells under conditions of starvation. We showed that loss of p53 – or parts of the p53 pathway – lead to a failure to cope with stress which can manifest in increased levels of damage or oxidative stress and reduced viability. We also explored the importance of serine in supporting cell viability and proliferation and showed that glycine cannot substitute for serine in supporting cell growth. This was an unexpected result and we were able to show this was due to the conversion of glycine to serine, and so depletion of one carbon units. We also found that the contribution of serine to the methylation cycle reflects both the supply of one carbon units and the de novo synthesis of ATP. We showed that an important function of p53 in these responses is to support antioxidant defence, an activity that can be mediated by several p53 target proteins including MDM2 and Tigar. Loss of these proteins results in excessing ROS under nutrient starvation which is detrimental to cell growth. We found that Tigar functions to control flux through the non-oxidative pentose phosphate pathway, so indirectly allowing NADPH production for antioxidant function through the oxidative pentose phosphate pathway. Importantly, we also examined the functions of p53 in vivo. To assist with these analyses, we developed models in which p53 activity could be directly measured through the activation of a fluorescent reporter protein. We showed that p53 can be protective under conditions of liver damage, helping to maintain metabolic homeostasis and limiting the development of fatty liver disease. Looking more specifically at the activity of the p53-target gene Tigar, we found that the antioxidant activity of Tigar was necessary to support tissue regeneration after damage and prevent early aging. Loss of Tigar resulted in increased oxidative stress, and to some extent the consequences of loss of Tigar were rescued by treatment of mice with an antioxidant. Taken together our work builds on the understanding of p53 as a stress response protein that participates in both allowing adaptation/survival in response to transient metabolic stress, as well as elimination of irreparably damaged cells. These results suggest that p53 function is much more broadly important than tumour suppression and indicate that modulation of p53 activity could also help to manage pathologies such as diabetes, obesity and normal aging.

Reported by

The Beatson Institute for Cancer Research
United Kingdom
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