The first 30 years of p53: growing ever more complex

Abstract

Thirty years ago p53 was discovered as a cellular partner of simian virus 40 large T-antigen, the oncoprotein of this tumour virus. The first decade of p53 research saw the cloning of p53 DNA and the realization that p53 is not an oncogene but a tumour suppressor that is very frequently mutated in human cancer. In the second decade of research, the function of p53 was uncovered: it is a transcription factor induced by stress, which can promote cell cycle arrest, apoptosis and senescence. In the third decade after its discovery new functions of this protein were revealed, including the regulation of metabolic pathways and cytokines that are required for embryo implantation. The fourth decade of research may see new p53-based drugs to treat cancer. What is next is anybody's guess.

Fig. 1. The first p53 workshop

The first p53 workshop took place at The Marie Curie Research Institute at The Chart in Oxted, Surrey, UK from 7-10 May 1983. The program did not include any presentation titles, but the hottest issued on the agenda were the first disclosures of the cloned murine p53 cDNA sequences, as well as reports on ongoing attempts to clone human p53 cDNA and genomic DNA. The table below shows the list of participants in the workshop. With some notable exceptions (David Lane), this was practically almost the entire p53 community in 1983. Program details and participant list courtesy of Varda Rotter.

Fig. 2. Simplified scheme of the p53 pathway

The p53-MDM2 feedback loop is the “heart” of the p53 pathway. Under normal conditions, it maintains p53 levels and activity at constantly low steady state levels. A variety of stress signals (only a representative subset of p53-activating signals are depicted), related in many ways to carcinogenesis, impinge on this central loop to release p53 from MDM2-mediated inhibition. This increases p53 protein levels and activity, inducing various phenotypic changes. Many p53-activating signals are closely interrelated, as exemplified here for oncogenes, whose impact on p53 is partly due to their propensity to induce DNA replication stress. The downstream effects of p53 are largely due to its ability to transactivate and repress various subsets of target genes; however, at least in the case of apoptosis, protein-protein interactions (primarily with Bcl2 family members) also play an important role. It is generally believed that the nature of the phenotypic response to p53 activation is, at least partially, proportionate to the amplitude, duration and nature of the activating signal. Severe stress induces more extreme, usually irreversible responses, namely apoptosis and senescence, whereas milder stress would lead to a transient growth arrest coupled with an attempt to deal with the cause of stress and repair the damage caused by it. Recent evidence indicates that p53 also has an important role in enabling the cell to adjust its metabolism in response to mild normal physiological fluctuations, including those in glucose and other nutrient levels, oxygen availability, and reactive oxygen species levels (see Focus by Vousden).