Modes of p53 regulation

Abstract

The traditional view of p53 activation includes three steps-p53 stabilization, DNA binding, and transcriptional activation. However, recent studies indicate that each step of p53 activation is more complex than originally anticipated. Moreover, both genetic studies in mice and in vitro studies with purified components suggest that the classical model may not be sufficient to explain all aspects of p53 activation in vivo. To reconcile these differences, we propose that antirepression, the release of p53 from repression by factors such as Mdm2 and MdmX, is a key step in the physiological activation of p53.

Figure 1. Overview of p53 Posttranslational Modifications

More than 36 amino acids of p53 are reported to be modified. The major sites of p53 phosphorylation (P), ubiquitination (Ub), and acetylation (Ac) are shown with the corresponding major modifying enzymes and signals. Furthermore, additional phosphorylation and acetylation sites, as well as major sites of methylation (Me), sumoylation (S), neddylation (N8), glycosylation (O-Glc), and ribosylation (ADP), are indicated.

Figure 2. Classical Model of p53 Activation

The classical model for p53 activation generally consists of three sequential activating steps: (1) stress-induced stabilization mediated by phosphorylation (P), (2) DNA binding, and (3) recruitment of the general transcriptional machinery. During normal homeostasis, p53 is degraded after Mdm2-mediated ubiquitination (left), while stress signal-induced p53 phosphorylation by ATM, ATR, and other kinases stabilizes p53 and promotes DNA binding. DNA-bound p53 then recruits the transcriptional machinery to activate transcription of p53 target genes.

Figure 3. p53 Acetylation and Target Gene Regulation

Upon stress-induced p53 activation, different sets of p53 target genes have different requirements for p53 posttranslational modifications. (A) A number of promoters can be activated by un-acetylated p53. This class of p53 target genes protects cells from excessive p53 activation. These target genes include Mdm2, Pirh2, and others. (B) The activation of genes involved in DNA repair and cell cycle control requires recruitment of specific histone acetyltransferases (HATs) and partial acetylation (Ac), acting at least in part by antirepression. (C) Full acetylation of p53 is required for the activation of proapoptotic genes. Activation of these targets induces a program to ensure efficient apoptosis.

Figure 4. Refined Model for p53 Activation

Promoter-specific p53 activation in vivo consists of three key steps: (1) p53 stabilization, (2) antirepression, and (3) promoter-specific activation. (1) Stress-induced p53 stabilization occurs through many different mechanisms, many of which act by affecting the ability of Mdm2 to ubiquitinate p53. (2) Antirepression describes the release of p53 from the repression mediated by Mdm2 and MdmX. This step requires the acetylation of p53 at key lysine residues and facilitates the activation of specific subsets of p53 targets. Phosphorylation of p53 or treatment with the small molecule Nutlin-3 may have similar effects on antirepression. (3) For full activation of specific promoters, p53 recruits and interacts with numerous cofactors. These act by modifying p53, the surrounding histones, or other transcription factors. Regulating the activation of specific groups of p53 targets for apoptosis, senescence, cell cycle control, DNA repair, autophagy, metabolism, or aging may require exact combinations of cofactors and posttranslational modifications. Abbreviations: Ac, acetylation; P, phosphorylation; Me, methylation; N8, neddylation; S, sumoylation.