p53 Research: the past thirty years and the next thirty years.

Thirty years of research on the p53 family of genes has generated almost fifty thousand publications. The first of these papers detected the p53 protein associated with a viral oncogene product in transformed cells and tumors and focused the field on cancer biology. Subsequent manuscripts have shown a wide variety of functions for the p53 family of genes and their proteins. These proteins are involved in reproduction, genomic repair, fidelity and recombination, the regulation of metabolic processes, longevity, surveillance of the stability of development, the production of stem cells and changes in epigenetic marks, the development of the nervous system (p73), the immune system (p73) and skin (p63), as well as the better known roles for the family in tumor suppression. The p53 family of genes has been found in the modern day ancestors of organisms with over one billion years of evolutionary history where they play a role in germ-line fidelity over that time span. As the body plan of the vertebrates emerged with the regeneration of tissues by stem cells over a lifetime, the p53 gene and its protein were adapted to be a tumor suppressor of somatic stem and progenitor cells complementing its' past functions in the germ line. Because the p53 family of genes has played a role in germ-line fidelity and preservation of the species, even in times of stress, these genes have been under constant selection pressure to change and adapt to new situations. This has given rise to this diversity of functions all working to preserve homeostatic processes that permit growth and reproduction in a world that is constantly challenging the fidelity of information transfer at each generation. The p53 family of gene products has influenced the rates of evolutionary change, just as evolutionary changes have altered the p53 family and its functions.