p53 post-translational modification: deregulated in tumorigenesis

Abstract

The p53 tumor suppressor protein has well-established roles in monitoring various types of stress signals by activating specific transcriptional targets that control cell cycle arrest and apoptosis, although some activities are also mediated in a transcription-independent manner. Here, we review the recent advances in our understanding of the wide spectrum of post-translational modifications that act as epigenetic-like codes for modulating specific functions of p53 in vivo and how deregulation of these modifications might contribute to tumorigenesis. We also discuss future research priorities to further understand p53 post-translational modifications and the interpretation of genetic data in appreciation of the increasing evidence that p53 regulates cellular metabolism, autophagy and many unconventional tumor suppressor activities.

Figure 1. Overview of p53 domain structure and post-translational modifications

The major sites for p53 phosphorylation, ubiquitination, neddylation, sumoylation, acetylation, and methylation are plotted. The enzymes responsible for each type of modification are shown on the right. Abbreviations: TAD, transactivation domain; PRD, proline rich domain; DBD, DNA-binding domain; TD, tetramerization domain; CRD, C-terminal regulatory domain.

Figure 2. Regulation of p53 stability and localization by ubiquitination

Nuclear p53 is targeted by Mdm2 for monoubiquitination promoting cytoplasmic translocalization or polyubiquitination promoting proteosomal degradation. The abundance of Mdm2 and MdmX are also regulated by ubiquitination and deubiquitination. HAUSP stabilizes p53, Mdm2, and MdmX through deubiquitination. In the cytoplasm, USP10 deubiquitinates monoubiquitinated p53, reversing nuclear export and recycling p53 into the nucleus. Monoubiquitinated p53 in the cytoplasm can possibly be further ubiquitinated by E4 ubiquitin ligases and targeted for degradation. Cytoplasmic p53 also has transcription-independent roles in activating apoptosis through permeabilization of the mitochondrial outer membrane and the inhibition of autophagy through mechanisms yet to be discovered. Abbreviations: U, Ubiquitination

Figure 3. Three-step activation of p53 transcriptional activity

p53 transcriptional activity is activated through three sequential steps: (i) DNA binding, (ii) anti-repression and (iii) cofactor recruitment. Under homeostasis, p53 is bound to target gene promoter DNA but is repressed by Mdm2 and MdmX. Cellular stress triggers phosphorylation and acetylation at key p53 residues and facilitates the release of p53 from Mdm2 and MdmX mediated repression. The exact combinations of cofactors and post-translational modifications present on p53 provide promoter specificity. Anti-repression alone is sufficient for the induction of the p53 negative feedback loop. Cell cycle control requires partial activation of p53 through further modifications. Apoptotic activation requires the full activation of p53 activity via specific cofactors and an array of modifications. The control of p53 transcriptional regulation of metabolism and autophagy remains to be understood. Important p53 target genes for each cellular outcome are listed on the right. Abbreviations: TFs, transcription factors; P, phosphorylation; Ac, acetylation.