Article

P53 a Jack of all trades but master of none

Department of Pathology and Helen Diller Family Comprehensive Cancer Centre, University of California San Francisco, 513 Parnassus Avenue, Room HSW-450A, UCSF Box 0502, San Francisco, California 94143-0502, USA.
Nature Reviews Cancer (Impact Factor: 37.4). 09/2009; 9(11):821-9. DOI: 10.1038/nrc2728
Source: PubMed

ABSTRACT

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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    • "This phenomenon is explained by an intrinsic, fail-safe mechanism whereby genetic events that stimulate cell cycle progression , like overexpression of Myc, sensitize cells to selfdestruct by triggering apoptosis. This concept can explain our inability to induce tumors by overexpressing Myc in mice with intact Tp53 because oncogene-induced apoptosis is often mediated by upregulated expression of Tp53[22]. As a surrogate for Tp53 loss, we expressed Bcl-2, a general and potent suppressor of apoptosis that is highly expressed in human medulloblastomas, in combination with Myc by RCAS transfer in Ntv-a mice[23,24]. "
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    • "The selective protection of normal tissues is possible because this strategy requires normal functioning p53 (Ganapathy et al., 2014aGanapathy et al., , 2014b ). Essentially all of the cancer cells have either mutated or dysfunctional p53 and therefore are not protected (Junttila and Evan, 2009). Importantly, it has been demonstrated that DNA damaging agent-induced p53 activity is inconsequential to the tumor suppressor function of p53, negating the concern that suppression of p53, even though temporary, could contribute to tumor development or progression (Christophorou et al., 2005Christophorou et al., , 2006). "
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