Census and evaluation of p53 target genes

Abstract

The tumor suppressor p53 functions primarily as a transcription factor. Mutation of the TP53 gene alters its response pathway, and is central to the development of many cancers. The discovery of a large number of p53 target genes, which confer p53's tumor suppressor function, has led to increasingly complex models of p53 function. Recent meta-analysis approaches, however, are simplifying our understanding of how p53 functions as a transcription factor. In the survey presented here, a total set of 3661 direct p53 target genes is identified that comprise 3509 potential targets from 13 high-throughput studies, and 346 target genes from individual gene analyses. Comparison of the p53 target genes reported in individual studies with those identified in 13 high-throughput studies reveals limited consistency. Here, p53 target genes have been evaluated based on the meta-analysis data, and the results show that high-confidence p53 target genes are involved in multiple cellular responses, including cell cycle arrest, DNA repair, apoptosis, metabolism, autophagy, mRNA translation and feedback mechanisms. However, many p53 target genes are identified only in a small number of studies and have a higher likelihood of being false positives. While numerous mechanisms have been proposed for mediating gene regulation in response to p53, recent advances in our understanding of p53 function show that p53 itself is solely an activator of transcription, and gene downregulation by p53 is indirect and requires p21. Taking into account the function of p53 as an activator of transcription, recent results point to an unsophisticated means of regulation.

Figure 1

Survey of 346 target genes derived from 319 individual gene studies. (a) The number of studies reporting individual p53 target genes published in a particular year. (b) Genes were reported as activated, repressed or both activated and repressed by p53. (c) Experiments were carried out in cells from human, mouse, rat or bovine. Some studies used cells from more than one species. (d) Binding of p53 is located in different parts of the gene. (e) p53 binding sites are located in varying distances from the TSS. Some genes display multiple p53 binding sites. (f) Various methods have been used to identify p53 binding sites. Some studies used more than one method. (g) The number of publications that used a particular method to identify p53 binding compared with the publication year. Some studies used multiple methods.

Figure 2

Survey of 3509 target genes derived from 16 high-throughput data sets. (a) The number of potential p53 targets is compared with the number of data sets that commonly identify them. (b) The number of genes is displayed that is identified by an increasing number of data sets as being directly activated by p53. (c) The number of genes is displayed that is identified by an increasing number of data sets as being directly repressed by p53.

Figure 3

Mechanisms of p53-mediated transcription control. (a) Mechanisms involving direct target gene activation by p53 and indirect repression through p53-p21-DREAM/RB are supported by genome-wide data. (b) Mechanisms involving the sequestration of coactivators or direct target gene repression by p53 are not supported by genome-wide data.

Figure 4

p53 directly activates target genes that mediate various functions. Proteins encoded by p53 target genes function in multiple processes that include, but are not limited to, cell cycle arrest, DNA repair, apoptosis, metabolism, autophagy, translation control and feedback mechanisms.