文章：

p53 -万事通，样样不精

p53 — a Jack of all trades but master of none

原文发布日期：2009-09-24

DOI: 10.1038/nrc2728

类型: Review Article

开放获取: 否

要点：

1. 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.
2. Vertebrate p53 is activated by many types of stress and damage. In its basal 'unactivated' state it also controls various normal physiological functions.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.

要点翻译：

1. p53是一种进化上古老的转录因子，其在早期后生动物中的原始功能可能是协调对应激和损伤的转录反应。
2. 脊椎动物p53可被多种类型的应激和损伤激活。在其基础的"未激活"状态下，它也控制着各种正常的生理功能。
3. 在脊椎动物中，p53作为重要的肿瘤抑制因子发挥作用，其本身或其相关的上游或下游通路在几乎所有癌症中均出现功能性失活。
4. p53在肿瘤抑制、应激或损伤反应以及正常生理中的作用在机制上的相互依赖或重叠程度尚不清楚。
5. 脊椎动物p53具有高度多效性，主导着多种条件性细胞反应。其中一些反应表面上看是相互对立的——例如，p53同时协调对基因毒性损伤的"暂停-修复-恢复"和"衰老和/或细胞死亡"反应。
6. 这种多功能性源于p53曲折的进化历程，并可能导致某些折衷，从而降低了p53作为肿瘤抑制因子的效力。
7. 脊椎动物中p53介导的肿瘤抑制的有效性依赖于p53通路被致癌信号持续可靠地激活，但从不被正常有丝分裂信号激活。
8. ARF肿瘤抑制因子似乎是癌细胞中p53激活的主要介质。ARF在进化中变得仅被致癌信号特异性诱导，这种信号是癌细胞在整个发生和后续进化过程中持续存在的固有特征。
9. 然而，在肿瘤细胞中触发ARF（从而触发p53通路）的并非生长信号的异常持续（这正是信号具有致癌性的原因），而是异常高的信号强度——这是致癌过程中常见但并非必然伴随的特征。
10. 因此，p53介导的肿瘤抑制在草率的进化过程中存在一个根本缺陷——它仅感知致癌信号的一个症状，而非致癌信号本身。

英文摘要：

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.

摘要翻译： 

癌症罕见，是因为它们的进化受到多种肿瘤抑制因子的主动遏制。其中，p53 显得尤为关键：几乎所有癌症都伴随着 p53 本身或其上下游通路的失活。p53 是后生动物应激反应的古老协调者，其肿瘤抑制功能可能是相对较晚的“借用”，只在大型、长寿生物获得足够体量和再生能力、需要专门机制约束失控增殖时才变得必需。然而，对这一古老转录因子的进化再利用也带来了妥协，限制了它作为肿瘤抑制因子的效力。

原文链接：

p53 — a Jack of all trades but master of none