Transcriptional regulation by p53

Abstract

Inactivation of p53 is critical for the formation of most tumors. Illumination of the key function(s) of p53 protein in protecting cells from becoming cancerous is therefore a worthy goal. Arguably p53's most important function is to act as a transcription factor that directly regulates perhaps several hundred of the cell's RNA polymerase II (RNAP II)-transcribed genes, and indirectly regulates thousands of others. Indeed p53 is the most well studied mammalian transcription factor. The p53 tetramer binds to its response element where it can recruit diverse transcriptional coregulators such as histone modifying enzymes, chromatin remodeling factors, subunits of the mediator complex, and components of general transcription machinery and preinitiation complex (PIC) to modulate RNAPII activity at target loci (Laptenko and Prives 2006). The p53 transcriptional program is regulated in a stimulus-specific fashion (Murray-Zmijewski et al. 2008; Vousden and Prives 2009), whereby distinct subsets of p53 target genes are induced in response to different p53-activating agents, likely allowing cells to tailor their response to different types of stress. How p53 is able to discriminate between these different loci is the subject of intense research. Here, we describe key aspects of the fundamentals of p53-mediated transcriptional regulation and target gene promoter selectivity.

Figure 1.

p53 lies at the center of a complex signalling network. In response to various inputs (top of figure), the p53 protein becomes stabilized. On stabilization of p53, various transcriptional outputs can be realized which may be determined by the strength of the p53 RE, the posttranslational modification status of p53, specific p53 binding partners, and the epigenetic landscape of the target gene promoter, among others. The transcriptional output of p53 is responsible for determining which cellular process(es) occur in response distinct genotoxic insults.

Figure 2.

p53 can modulate transcription intiation and elongation at RNAPII-transcribed loci. p53 can direct preinitiation complex (PIC) assembly at certain target gene promoters under basal conditions, and at others only in response to stress. This process involves the ordered recruitment of histone methyltransferases (HMTs), histone acetyltransferase (HATs), and other coregulators in the vicinity of the p53 response element (RE) to open up chromatin so that RNAPII and its associated general transcription factors (GTFs) can bind to the transcription start site of the locus. In response to specific stimuli, p53 can also modulate transcription elongation via functional and physical interactions with various elongation factors.

Figure 3.

p53 target genes are regulated in a stimulus-, locus-, and context-specific manner. In cell types A and B, both locus X and Y exhibit similar amounts of bound p53, however, their transcriptional output differs. Stress 1 is able to induce a cellular environment where coactivators A and B are available. At locus X in cell type A, this produces a strong transcriptional response because both coactivators can bind; however, in cell type B, locus X is methylated and thus is not transcribed. Locus Y in cell types A and B cannot recruit recruit coactivator B, resulting in only a moderate transcriptional output. Stress 2 induces a transcriptional environment where coactivator B and corepressor C are available. Locus X does not contain a binding site for corepressor C, and therefore the transcriptional ouput is moderate. Locus Y, on the other hand, does contain a binding site for corepressor C, whose binding prevents the strong transactivation of gene Y in both cell types, despite high levels of bound p53.

Figure 4.

Selective impact of p53 modifications on transactivation Several examples are depicted of residues within p53 that can be modified by acetylation (orange), phosphorylation (red), ubiquitylation (green), or methylation (purple). The preferential activation of the indicated target genes (and others, not depicted) can result in specific cell fates, such as apoptosis or cell cycle arrest.

Figure 5.

p53 target genes and cellular outcomes can be influenced by p53 binding partners. P53 activity can be modulated by different binding partners to induce differential transactivation of target genes and outcome. Proteins that interact with the TADs, the DNA binding core, the tetramerization domain, and the CTD are shown. Hzf, Brn3a, c-abl, Muc1 YB1, APAK, and BRCA1 induce a transcriptional program that facilitates cell cycle arrest, whereas Strap, JMY, Pin1, ASPP1 and ASPP2, p53β, NFκB/p52, and Brn3b induce a program that promotes apoptosis.