P53

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p53

The p53 protein lies at the heart of stress response pathways that prevent the growth and survival of potentially malignant cells. Many types of stress activate p53, including DNA damage, telomere attrition, oncogene activation, hypoxia and loss of normal growth and survival signals. These stress signals may be encountered by a developing malignancy at several stages during tumorigenesis, from initiation of the tumor to invasion and metastasis. It therefore seems likely that p53 plays a role in preventing tumor cell growth at several points during the malignant process, explaining why loss of p53 function has such a profound effect on tumor development.

p53 is a sequence-specific transcription factor that can mediate many of its downstream effects by the activation or repression of target genes. Activation of p53 can induce several responses in cells, including differentiation, senescence, DNA repair and the inhibition of angiogenesis, but best understood is the ability of p53 to induce cell cycle arrest and apoptotic cell death. These two responses allow p53 to inhibit the growth of stressed cells either by a cycle arrest, which may be irreversible or transient to allow repair and recovery before further rounds of replication, or by permanent removal of these cells from the organism by apoptosis. Either response would prevent replication of cells undergoing oncogenic changes and so would inhibit tumor development.

Despite the importance of transcriptional regulation, however, transcriptionally independent activities of p53 also play a role in mediating at least some of its downstream effects, most notably the induction of apoptosis. These functions of p53 include the relocalization of death receptors to the cell surface, a direct role for p53 in the mitochondria and an ability of p53 to regulate translation by direct binding to the 5′ untranslated region of certain mRNAs. Numerous p53-dependent target genes have been identified that play a role as downstream effectors of each p53 function. For example, the cyclin dependent kinase inhibitor p21Waf1/Cip1 is a direct p53 target and deletion of this gene significantly reduces the cell cycle arrest response to p53. More recently, the ability of p53 to participate directly in DNA repair has been shown to be associated with the activation of a ribonucleotide reductase, named p53R2.

Although a physiological role for p53 in aging is controversial, studies with different mouse models indicate a delicate balance between the tumor suppressive and agepromoting functions of p53. apoptosis and cellular senescence can lead to aging phenotypes, possibly by depletion of important stem cell and other stromal cell pools. Thus, integration of DNA damage signaling by p53 has been optimized to balance the beneficial effects of tumor suppression against the detrimental effects of tissue degeneration. . Insights into the role of p53 in aging are also derived from studies of human populations. Human p53 has a Pro/Arg polymorphism at amino acid residue 72. Humans carrying one or two copies of the Pro or Arg p53 form have been studied for cancer susceptibility, mortality and survival. p53Arg is a more potent inducer of apoptosis than the p53Pro form. A prospective study done by the same group in 1226 subjects aged 85 or over showed that the Pro/Pro carriers had a 41% increased survival, despite a 2.54-fold increase in cancer mortality, compared to the Arg/Arg carriers. The authors suggested that in older survivors, p53Arg protected against cancer more efficiently than p53Pro but at the cost of a diminished life span.