Posttranslational modification of p53: cooperative integrators of function

Abstract

The p53 protein is modified by as many as 50 individual posttranslational modifications. Many of these occur in response to genotoxic or nongenotoxic stresses and show interdependence, such that one or more modifications can nucleate subsequent events. This interdependent nature suggests a pathway that operates through multiple cooperative events as opposed to distinct functions for individual, isolated modifications. This concept, supported by recent investigations, which provide exquisite detail as to how various modifications mediate precise protein-protein interactions in a cooperative manner, may explain why knockin mice expressing p53 proteins substituted at one or just a few sites of modification typically show only subtle effects on p53 function. The present article focuses on recent, exciting progress and develops the idea that the impact of modification on p53 function is achieved through collective and integrated events.

Figure 1.

Posttranslational modification of human p53. The figure is updated from Anderson and Appella (Anderson and Appella 2009). The principal functional domains of p53 are shown together with the sites of modification and their potential modifying and demodifying enzymes.

Figure 2.

Multisite phosphorylation of the amino terminus of p53 regulates the interaction with MDM2 and with p300/CBP. “Wrap around” model proposed by Fersht and colleagues (Teufel et al. 2007) for the simultaneous binding of one monomer of p300/CBP to tetrameric p53. These interactions are stimulated by multisite phosphorylation of the amino terminus of p53.

Figure 3.

Mutually exclusive binding of MDM2 and p300/CBP to p53. Four similar subdomains of p300 (Taz1, Taz2, Kix, and IBiD) can each simultaneously bind to the TAD1 and TAD2 transactivation subdomains of p53. Binding to TAD2 is essentially phosphorylation-independent but multisite phosphorylation within TAD1 greatly stimulates its interaction with p300 but blocks association with MDM2. p300 acts as a scaffold in mediating MDM2-dependent ubiquitylation and degradation of p53: Concurrent binding of MDM2 to TAD1 and p300 to TAD2 may facilitate p53 turnover.

Figure 4.

Sequential multiple modifications may act as a switch that excludes MDM2 binding in favor of interaction with transcriptional proteins. Multisite phosphorylation of the amino terminus of p53 blocks the interaction with MDM2 and favors recruitment of the HATs p300 and CBP that subsequently can acetylate numerous lysine residues in p53, further adding to the exclusion of MDM2 and favoring the engagement of transcriptional components.

Figure 5.

Phosphorylation and function of serines 6 and 9 in p53. Phosphorylation of Ser6 and Ser9 in p53 integrates TGF-β- and FGF-signaling by promoting the interaction of p53 with Smad2. These residues are also modified in response to various genotoxic and nongenotoxic stresses, but their function in this context is not yet defined.