p53 at a glance

Abstract

Since its discovery in 1979, the role of the p53 protein in cancer has been studied intensively (Levine and Oren, 2009). p53 is a crucial tumor suppressor, long-recognized to suppress cancer through the induction of cell-cycle-arrest or apoptosis programs in response to a plethora of different cellular stress signals. Although this model paints a seemingly simple picture, the longer that p53 is studied, the more it confronts researchers with new questions about its functions and mechanisms of action. The tumor-suppressor function of p53 extends beyond the capacity to trigger cell-cycle arrest and apoptosis, and novel activities that impact tumor suppression are perpetually emerging, including the regulation of metabolism, autophagy and the oxidative status of the cell. Moreover, because it acts as a crucial node downstream of diverse stress signals, it is perhaps not surprising that p53 has been recently discovered to have broader roles in physiology and pathology. In this article and its accompanying poster, we outline the basic molecular and cellular functions of p53, describe the intricate network of p53 mediators, and provide insight into the roles of p53 in normal physiology and human disease.Analysis of human cancers reveals a fundamental role for p53 in tumor suppression. More than half of human cancers, of a wide variety of types, harbor p53 (TP53) mutations, and inheritance of a mutant p53 allele predisposes humans to the Li-Fraumeni cancer syndrome (Olivier et al., 2010). Unequivocal confirmation of the crucial role for p53 in tumor suppression was demonstrated by the completely penetrant cancer phenotype of p53-null mice (Kenzelmann Broz and Attardi, 2010). p53 restricts tumor development by serving as a sensor of cellular stress, responding to diverse signals, including DNA damage, hypoxia, oncogene expression, nutrient deprivation and ribosome dysfunction, and limiting the propagation of cells under these adverse conditions (Vousden and Prives, 2009). In metazoans, an ancestral function of p53 is thought to be its ability to trigger programmed cell death (also known as apoptosis) in response to DNA damage, as a measure to preserve the integrity of the germ line (Junttila and Evan, 2009; Lu and Abrams, 2006; Lu et al., 2009). Subsequently, with the evolution of longer-living organisms, p53 is thought to have acquired the ability to respond to oncogenic signals, promoting apoptosis or senescence – a permanent cell-cycle-arrest response – as a safeguard against neoplasia. Thus, in cells exposed to potent stress signals, p53 drives irreversible programs of apoptosis or senescence to cull irreparably damaged or malignant cells, for the ultimate benefit of the organism (Vousden and Prives, 2009). Alternatively, under conditions of low-level stress, p53 elicits protective, pro-survival responses, such as temporary cell-cycle arrest, DNA repair and antioxidant protein production, to maintain genome integrity and viability in cells that sustain limited, reparable damage. These various responses rely on the ability of p53 to function as a transcriptional activator of a panoply of target genes, although transactivation-independent activities ascribed to p53 can also contribute to p53-mediated responses, as highlighted below.Similarly to other transcription factors, p53 has a modular protein domain structure (Joerger and Fersht, 2007; Vousden and Prives, 2009). The N-terminus of p53 comprises two transcriptional activation domains (TADs), TAD1 and TAD2, which span amino acid residues 1-40 and 40-60, respectively. These domains can independently enhance transcription of p53 target genes by recruiting histone-modifying enzymes, components of the basal transcriptional machinery and coactivator complexes, such as STAGA and Mediator (Gamper and Roeder, 2008; Joerger and Fersht, 2007). C-terminal to the transactivation domains, between residues 60-95, lies the proline-rich domain (PRD), which was originally proposed to participate in protein-protein interactions on the basis of the presence of PxxP motifs that resemble Src homology 3 (SH3)-domain-binding regions (Toledo et al., 2006; Toledo et al., 2007). However, a structural function might be the main role of this domain because knock-in mice carrying proline-to-alanine point mutations in the putative protein-protein interaction sites of this domain appear normal, whereas complete domain deletion disrupts p53 tumor-suppressor function. The central core of p53, which spans residues 100-300, comprises the DNA-binding domain that is responsible for sequence-specific binding of the protein to p53 response elements in DNA. Most cancer-associated p53 mutations are missense mutations in this domain and incapacitate DNA binding, illuminating the key importance of DNA binding for p53-mediated tumor suppression. Tumor-derived p53 mutations either alter residues that are essential for direct contact with p53 response elements (contact mutants) or impair proper folding of