ncRNAs in p53 Regulation
Salah Mahmoudi, Anna Vilborg and Marianne Farnebo
from: Non-coding RNAs and Epigenetic Regulation of Gene Expression: Drivers of Natural Selection (Edited by: Kevin V. Morris). Caister Academic Press, U.K. (2012)
The p53 tumor suppressor is arguably the most important player in preventing tumor formation and progression. p53 mutations are found with high frequency (about 50%) in human tumors, however virtually all tumors have inactivated the p53 pathway in some fashion.The p53 protein functions as a transcription factor with a crucial role in orchestrating the cellular stress response. p53 can be activated by a large variety of stress factors, and reacts by triggering an appropriate response, the nature of which will vary with the triggering factor and the cellular background. The most classical outcomes of p53 activation are cell cycle arrest and apoptosis, and it is generally believed that these two, together with senescence, irreversible cell cycle arrest, are the p53 responses with greatest impact on preventing tumor formation2. However, it has lately become evident that p53 is involved in many other processes in addition to these. p53 can promote several forms of DNA repair, thus contributing to maintaining genomic integrity. Further, p53 may promote differentiation of stem and progenitor cells into more specialized cell types, and can also prevent self-renewal of stem cells. Paradoxically, p53 can also induce genes involved in promoting survival. One of these genes is p21, while being a classical cell cycle arrest-inducing p53 target, p21 antagonizes apoptosis. The list of pro-survival p53 targets also includes several antioxidant genes and genes involved in metabolism. The logic behind this surprising p53 function may be that the elimination of every cell ever exposed to any kind of stress is not desirable, while protecting us from getting cancer, it would lead to tissue degeneration. In addition to its crucial role in cancer, p53 has been implicated in several other diseases, generally diseases connected to excessive cell death. These include diabetes, cell death after ischemia, and various neurodegenerative diseases such as Huntington, Parkinson, and Alzheimer. Since p53 is able to eliminate cells through apoptosis and senescence and to induce differentiation, thus reducing stem cell populations, p53 has also been suggested to promote aging. Initial studies in mice expressing constitutively active p53 also seemed to confirm this hypothesis, However, subsequent mice models carrying an extra copy of p53 but under control of its normal regulatory elements demonstrated that properly controlled p53 did not induce aging. Instead it actually promoted longevity, largely by preventing tumorigenesis. Due to its critical function in deciding on life or death for the cell, strict regulation of p53 levels and activity is crucial. p53 protein levels are kept under tight control by multiple mechanisms. Further, p53 mRNA stability and translation is subject to regulation by a number of factors, including long non-coding RNA read more ...