p53 is an evolutionary ancient transcription factor, the primordial function of which in early metazoans may have been to coordinate transcriptional responses to stress and damage.
Vertebrate p53 is activated by many types of stress and damage. In its basal 'unactivated' state it also controls various normal physiological functions.
In vertebrates, p53 acts as an important tumour suppressor and either it or its attendant upstream or downstream pathways are functionally inactivated in virtually all cancers.
The extent to which the roles of p53 in tumour suppression, stress or damage responses and normal physiology are interdependent or overlap mechanistically is unclear.
Vertebrate p53 is highly pleiotropic and presides over a diverse range of contingent cell responses. Some of these responses are ostensibly antithetical — for example, p53 coordinates both the 'pause–repair–recovery' and 'senescence and/or cell death' responses to genotoxic injury.
Such multifunctionality arises from the tortuous evolutionary legacy of p53, and may have led to compromises that degrade the efficacy of p53 as a tumour suppressor.
The effectiveness of p53-mediated tumour suppression in vertebrates relies on the consistent and reliable activation of the p53 pathway by oncogenic signalling but never by normal mitogenic signals.
The ARF tumour suppressor seems to be the pre-eminent mediator of p53 activation in cancer cells. ARF has evolved to be specifically induced only by oncogenic signals, which are persistent and obligate attributes of cancer cells throughout their genesis and subsequent evolution.
However, the trigger for ARF (and hence, the p53 pathway) in tumour cells is not the abnormal persistence of growth signals, which is what makes signals oncogenic, but the aberrantly high signal strength, which is a frequent — but not unfailing — correlate of oncogenesis.
Therefore, the slapdash evolution of p53-mediated tumour suppression has incorporated a fundamental flaw — it senses only a symptom of oncogenic signalling rather than the oncogenic signal itself.
Cancers are rare because their evolution is actively restrained by a range of tumour suppressors. Of these p53 seems unusually crucial as either it or its attendant upstream or downstream pathways are inactivated in virtually all cancers. p53 is an evolutionarily ancient coordinator of metazoan stress responses. Its role in tumour suppression is likely to be a relatively recent adaptation, which is only necessary when large, long-lived organisms acquired the sufficient size and somatic regenerative capacity to necessitate specific mechanisms to reign in rogue proliferating cells. However, such evolutionary reappropriation of this venerable transcription factor entails compromises that restrict its efficacy as a tumour suppressor.
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The authors thank the Ellison Medical Foundation for support. Melissa R. Junttila is the Enrique Cepero, Ph.D. Fellow of the Damon Runyon Cancer Research Foundation.
NCI Nature Protein Interaction Database (PID)
Cinidarians comprise an animal phylum of ∼9,000 radially symmetrical, mostly marine organisms. Most other animals are bilaterally symmetrical and are classed as bilateria. The cnidarians and bilaterians last shared a common ancestor ∼570–700 million years ago.
Interference of one transcriptional activator by another is called squelching, and is caused by competition for binding a scarce factor.
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Junttila, M., Evan, G. p53 — a Jack of all trades but master of none. Nat Rev Cancer 9, 821–829 (2009). https://doi.org/10.1038/nrc2728
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