ReviewRegulation and function of the p53 tumor suppressor protein
Introduction
p53 has been the subject of intense research activity over the past 10 years because of its critical role in guarding against cancer development [1]. Although mice deleted for p53 can develop normally, they are highly tumor prone, and loss of p53 strongly enhances tumor development driven by other oncogenic alterations. Around half of all human cancers carry p53 mutations, and recent studies have suggested that many tumors that retain wild-type p53 are defective in either the ability to induce or the ability to respond to 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.
Activation of p53 can induce several responses in cells, including differentiation, senescence, DNArepair and the inhibition of angiogenesis, but best understood is the ability of p53 to induce cell cycle arrest and apoptotic cell death [2]. 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.
Section snippets
Functions of p53: regulation of gene expression
p53 is a sequence-specific transcription factor that can mediate many of its downstream effects by the activation or repression of target genes. A large body of evidence supports the importance of these activities for p53 function, including recent studies showing that substitution of a gene encoding a transcriptionally inactive mutant p53 for the wild-type gene in mice leads to loss of growth inhibitory activity 3•., 4•.. Despite the importance of transcriptional regulation, however,
Keeping p53 under control
As p53 is such a potent inhibitor of cell growth, its function must be tightly controlled to allow normal growth development. This is achieved through several mechanisms that include regulation of p53 transcription and translation, protein stability, subcellular localization and activity [19]. Rapid induction of p53 function is achieved in response to most forms of stress through post-translational mechanisms, leading to the stabilization and activation of the p53 protein.
Allowing normal proliferation
The induction of p53 in response to oncogenes such as Myc, Ras and E2F1 provides an efficient mechanism to prevent the outgrowth of cells that show proliferative abnormalities. However, activation of these same signals is also required for normal cell proliferation and several mechanisms that attenuate the p53 response to allow normal cell division have been described. For example, Ras activation leads to the transcriptional activation of MDM2, which would counteract the Ras-induced elevation
Conclusions
Remarkable progress has been made in defining how p53 function is regulated, determining the pathways that can activate p53 and identifying the downstream mediators of the p53 response. These advances have brought with them the realization that there are many ways to perturb the p53 pathway during tumor development, in addition to the commonly seen mutation within the p53 gene itself. These include loss of the ability to stabilize p53, through mechanisms such as loss of ARF or inactivation of
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
•of special interest
••of outstanding interest
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