More targets, more pathways and more clues for mutant p53

S Garritano,S Landi,A Inga,F Gemignani

doi:10.1038/oncsis.2013.15

Abstract

Mutations in the transcription factor p53 are among the most common genetic alterations in human cancer, and missense p53 mutations in cancer cells can lead to aggressive phenotypes. So far, only few studies investigated transcriptional reprogramming under mutant p53 expression as a means to identify deregulated targets and pathways. A review of the literature was carried out focusing on mutant p53-dependent transcriptome changes with the aims of (i) verifying whether different p53 mutations can be equivalent for their effects, or whether there is a mutation-specific transcriptional reprogramming of target genes, (ii) understanding what is the main mechanism at the basis of upregulation or downregulation of gene expression under the p53 mutant background, (iii) identifying novel candidate target genes of WT and/or mutant p53 and (iv) defining cellular pathways affected by the mutant p53-dependent gene expression reprogramming. Nearly 600 genes were consistently found upregulated or downregulated upon ectopic expression of mutant p53, regardless of the specific p53 mutation studied. Promoter analysis and the use of ChIP-seq data indicate that, for most genes, the expression changes could be ascribed to a loss both of WT p53 transcriptional activation and repressor functions. Pathway analysis indicated changes in the metabolism/catabolism of amino acids such as aspartate, glutamate, arginine and proline. Novel p53 candidate target genes were also identified, including ARID3B, ARNT2, CLMN, FADS1, FTH1, KPNA2, LPHN2, PARD6B, PDE4C, PIAS2, PRPF40A, PYGL and RHOBTB2, involved in the metabolism, xenobiotic responses and cell differentiation.

Highlights

It acts as a transcription factor3 and modulates the expression of a variety of genes, leading to enhanced DNA repair, control of cell cycle and apoptosis, and maintaining cellular homeostasis
CDKN1A, MDM2, BAX, GADD45 and BBC3 are paradigmatic examples of upregulated target genes where p53 exerts its activity via evolutionarily conserved cis-response elements (p53RE)
In this work, the focus was placed on cancer-associated p53 hotspot mutations that exhibit a loss of transactivation function in reconstituted assays,12,14 and a review of the literature was performed, with the following aims: (1) to verify whether different p53 mutations can be equivalent for their effects, or whether there is a mutation-specific transcriptional reprogramming of target genes, (2) to understand what is the main mechanism at the basis of upregulation or downregulation of gene expression under the p53 mutant background, (3) to identify the novel candidate target genes of WT and/or mutant p53 and (4) to define cellular pathways affected by the mutant p53-dependent gene expression reprogramming

Summary

INTRODUCTION

The tumor suppressor p53 is a 393-amino-acid nuclear phosphoprotein that responds to numerous stress stimuli, including DNA damage and hypoxia. Following homotetramerization, it acts as a transcription factor and modulates the expression of a variety of genes, leading to enhanced DNA repair, control of cell cycle and apoptosis, and maintaining cellular homeostasis. The p53 targets are only partially known, with assessments suggesting their number to be nearly 2000 genes.. In this work, the focus was placed on cancer-associated p53 hotspot mutations that exhibit a loss of transactivation function in reconstituted assays, and a review of the literature was performed, with the following aims: (1) to verify whether different p53 mutations can be equivalent for their effects, or whether there is a mutation-specific transcriptional reprogramming of target genes, (2) to understand what is the main mechanism at the basis of upregulation or downregulation of gene expression under the p53 mutant background, (3) to identify the novel candidate target genes of WT and/or mutant p53 and (4) to define cellular pathways affected by the mutant p53-dependent gene expression reprogramming. Out of over 2000 known p53 mutations reported by the IARC (www.iarc.fr/p53) or UMD TP53 databases, only 12, falling in 11 different codon sites (Figure 1), were studied through global gene expression changes Those 11 mutated codons lie within the sequence-specific DNA-binding domain, correspond to hotspot mutations in tumors and result in LOF in functional assays.

RESULTS AND DISCUSSION

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CONFLICT OF INTEREST