The role of NMNAT2, a new p53 target gene, in feedback regulation of p53 function via the SIRT deacetylases.

The cells in our body are constantly exposed to environmental factors (e.g. UV light, chemical carcinogens in the air, food, or cigarettes) that could do major damage to our DNA. If the cell did not do anything about it, the damaged DNA would be passed onto subsequent generations of cells, and could eventually lead to cancer development. To prevent this from happening, the cell uses a protein called p53 that acts as a policeman. Upon DNA damage, this protein tells the cell to immediately stop growing, allowing time to repair this damage; or, should the damage be too severe, to commit suicide by triggering a cellular process called apoptosis. In either case, the damaged DNA would not be passed onto future cell populations. P53 therefore serves a very important function, and loss of p53 itself or its function has been found in over 50% of all human cancers. How p53 carries out all these important tumour suppressing functions has been an area of intense research as it may reveal how we get cancer and how we can control cancer. At the molecular level, the chain of command from p53 down has been well studied, however, major gaps in knowledge remain. The proposed research is based on our recent discovery of a new protein whose synthesis is under the control of p53, and that this new protein, called Nmnat2, can in turn loop back and control p53's cell killing function. We consider this to be a major revelation in the p53 field, and propose a series of experiments that will define the precise relationship between Nmnat2 and p53, which should in turn shed light on the mechanism whereby p53 controls cancer development as well as other metabolic processes in the cell. The long term objective of this study is to determine if any human cancers and metabolic disorders can be traced to defects in the Nmnat2-p53 regulatory loop, and to develop specific strategies against such diseases.