In 1979, the discovery of p53 was reported. Once it was discovered that TP53 (the human p53 gene) is one of the most commonly mutated tumour suppressor genes in human cancer, a new research field was born. p53 functions as a node in numerous signalling pathways such that it regulates many important biological activities — from fertility and development to maintaining genomic stability and cell death.
New revelations about the function of p53 have not declined with age. For example, within the past 15 years p53 has been shown to be part of a family that can be subject to alternative splicing. The fact that p53 was originally described as an oncogene has recently come full circle with mutant p53 having been shown to exhibit gain–of–function properties that actually drive tumour progression and metastasis. However, as the diversity of p53–dependent activities widens to include key roles in metabolism and development old debates continue, such as how does p53 function to suppress tumour development or activate its target genes? And, crucially, how is the mutation of other oncogenes detected by the p53 pathway? One thing is clear, p53 is therapeutically important and numerous strategies are being employed to reconstitute its expression in tumours.
The articles in this Focus on p53 — 30 years on, together with some recent Research Highlights and the accompanying library of the most relevant recent publications from Nature Research, describe our current understanding of this field.
Research Highlights
Therapeutics: One and one makes...
Nicola McCarthy
doi:10.1038/nrc2740
Nature Reviews Cancer 9, 686-687 (2009)
Senescence: The more the merrier
Sophie Atkinson
doi:10.1038/nrc2737
Nature Reviews Cancer 9, 688-689 (2009)
Chondrosarcoma: p53 and Gli combine forces
Sarah Seton-Rogers
doi:10.1038/nrc2741
Nature Reviews Cancer 9, 688-689 (2009)
Transcription: Reaching a consensus
Nicola McCarthy
doi:10.1038/nrc2743
Nature Reviews Cancer 9, 689 (2009)
Reviews
p53 and metabolism
Karen H. Vousden & Kevin M. Ryan
doi:10.1038/nrc2715
Nature Reviews Cancer 9, 691-700 (2009)
p53 can regulate numerous aspects of metabolic pathways and thereby influence the metabolic alterations exhibited by tumour cells. However, the contribution of p53 is complex and in some cases might promote, rather than inhibit, tumour progression. So, just what is p53 doing?
When mutants gain new powers: news from the mutant p53 field
Ran Brosh & Varda Rotter
doi:10.1038/nrc2693
Nature Reviews Cancer 9, 701-713 (2009)
Mutant p53 proteins not only lose their tumour suppressive ability, but also gain new properties that promote tumorigenesis. What are these properties and what are the clinical implications?
Tumour suppression by p53: a role for the DNA damage response?
David W. Meek
doi:10.1038/nrc2716
Nature Reviews Cancer 9, 714-723 (2009)
How important is the DNA damage response in mobilizing the tumour suppression function of p53? This Review considers how supporting and conflicting evidence about the role of DNA damage response signalling in cancer can be reconciled.
The expanding universe of p53 targets
Daniel Menendez, Alberto Inga & Michael A. Resnick
doi:10.1038/nrc2730
Nature Reviews Cancer 9, 724-737 (2009)
Target response element sequences are a crucial part of the p53 network. This Review describes how functional response elements can be defined and discusses the implications of non-canonical p53 response elements, which greatly expand the universe of p53-regulated genes, on the part that p53 plays as a tumour suppressor.
p53 and E2f: partners in life and death
Shirley Polager & Doron Ginsberg
doi:10.1038/nrc2718
Nature Reviews Cancer 9, 738-748 (2009)
The Rb–E2f and MDM2–p53 pathways are both defective in most human tumours, indicating that these pathways function independently in the control of cell fate. However, extensive crosstalk between these two pathways also exists. How do they coordinately affect tumour biology?
p53 — a Jack of all trades but master of none
Melissa R. Junttila & Gerard I. Evan
doi:10.1038/nrc2728
Nature Reviews Cancer 9, 821-829 (2009)
Advance online publication, 24 September 2009p53 is an evolutionarily ancient coordinator of metazoan stress responses and its role in tumour suppression is likely to be a relatively recent adaptation. This Review discusses how such evolutionary retooling of this venerable transcription factor entails compromises that restrict its efficacy as a tumour suppressor.
Perspectives
The first 30 years of p53: growing ever more complex
Arnold J. Levine & Moshe Oren
doi:10.1038/nrc2723
Nature Reviews Cancer 9, 749-758 (2009)
When p53 was first discovered, it received relatively little attention from cancer researchers. The road leading to p53's rise to fame, and the recognition of TP53 as the most frequently altered gene in human cancer, has been long and winding. This Timeline examines the rich history of this pivotal tumour suppressor.
p53 ancestry: gazing through an evolutionary lens
Wan-Jin Lu, James F. Amatruda & John M. Abrams
doi:10.1038/nrc2732
Nature Reviews Cancer 9, 758-762 (2009)
The selective pressures for the retention of primordial p53 genes predated the appearance of cancer. Therefore, wild-type tumour suppressive functions were probably co-opted from unrelated primordial activities. Is it possible to deduce what these early functions might have been?
20 years studying p53 functions in genetically engineered mice
Lawrence A. Donehower & Guillermina Lozano
doi:10.1038/nrc2731
Nature Reviews Cancer 9, 831-841 (2009)
Understanding the activities of p53 in tumour suppression and in other processes has been substantially aided by the use of mouse models. How have these models evolved and what have they taught us about p53 and tumour suppression?
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