Celebrating 30 years of p53 research

Abstract

In 1979, the transcription factor p53 was identified as a humble smudge on an SDS-PAGE gel, so we are now in the 30th year that it has been under investigation. The intervening 30 years have seen astonishing developments in many areas – think of the transition from the Walkman of 1979 to the iPod Nano of today – but the growth in our understanding of p53 functions has kept pace and is leading to real prospects of manipulating p53-dependent pathways for therapeutic benefit.Although p53 was originally thought to be an oncogene, it was ‘rediscovered’ as a tumour suppressor in the mid-1980s. Since then, it has enjoyed considerable ‘media glare’ as the target gene of pivotal loss-of-function mutations in many human cancers. p53's many roles in the cell, in both health and disease, are still being elucidated by experts all over the world today.To celebrate this milestone, we are publishing a series of Reviews throughout 2010 to provide in-depth analyses of the latest developments in the p53 field. Experts from a wide range of disciplines – reflecting the diverse processes that p53 is involved in – will contribute to this series. The reviews will highlight latest research into the roles of p53 in cell cycle control, apoptosis, metabolism, autophagy, differentiation and cellular reprogramming.To kick off the series, this issue features an article by Daniel Speidel focusing on new evidence that p53 can trigger apoptosis via non-transcriptional mechanisms. Apoptosis induced by p53 has long been established as a central mechanism of tumour suppression. It was generally thought that this role was carried out by p53's transcriptional regulation activities. Now, it is becoming clear that the cytoplasm and the mitochondria are also sites of p53 action during the initiation of programmed cell death. These results also open up novel angles for targeted anti-cancer therapeutics.Forthcoming in March's issue, Yang Xu will give insight into the exciting new data about impact of p53 in on stem cells and reprogramming. The new findings heighten concern about genomic instability and tumourigenecity of iPSCs and their derivatives, and may have important implications for the use of iPSCs in vivo. These findings also will help us to understand how p53 coordinates tumour suppression and aging.Later issues of TCB throughout the year will feature articles from more leaders in the p53 field. Geoff Wahl and colleagues will discuss new insights into how p53 interacts with Mdm2 and Mdmx, its two main negative regulators. A topic that has garnered much attention in recent times is the process of autophagy (‘self-eating’) and Maureen Murphy will provide an update on the roles that p53 and its interaction partner Arf play in autophagy.As well as losing the protective ‘guardian of the genome’ functions of p53, cancer cells can often progress to malignancy with mutated p53 proteins that actively promote carcinogenesis. Interestingly, this brings the field full circle to the view of the early 1980s that TP53 can function as an oncogene. Ted Hupp will give an account of the pathological consequences of mutant p53 ‘gain of function’ processes in tumourigenesis. Rounding off the series with one of the pioneers of the p53 field, Arnold Levine will discuss the importance of p53 in metabolic pathways.While taking stock of the field, it is also tempting to forecast what we may know about p53 in another few decades. So what has this talented protein left to reveal? From the basic cell biology perspective, it will be interesting to witness the growing “p53-ome” of interaction partners and signaling pathways still to be characterized. And with respect to the clinical implications of a deeper understanding of the mechanisms of function of p53, broader problems will also need to be solved. So for example, will gene therapy have come of age? Stem cell therapy likewise may have transferred from the bench to the clinic, providing an alternative approach to individualized medicine; the status of the p53 pathway may prove to be a major consideration in cell-based approaches. These and other provocative questions will keep the wider community extremely busy for many years, and we await future developments with great anticipation. One thing is certain: teasing apart the intricate cell biology of p53 will provide a vital tool for developing therapeutic interventions in a range of cancers and inherited syndromes.We hope you will enjoy the articles in this series and of course welcome your feedback.Happy Birthday p53!