Surf the post-translational modification network of p53 regulation

Abstract

Among the human genome, p53 is one of the first tumor suppressor genes to be discovered. It has a wide range of functions covering cell cycle control, apoptosis, genome integrity maintenance, metabolism, fertility, cellular reprogramming and autophagy. Although different possible underlying mechanisms for p53 regulation have been proposed for decades, none of them is conclusive. While much literature focuses on the importance of individual post-translational modifications, further explorations indicate a new layer of p53 coordination through the interplay of the modifications, which builds up a complex 'network'. This review focuses on the necessity, characteristics and mechanisms of the crosstalk among post-translational modifications and its effects on the precise and selective behavior of p53.

Keywords: crosstalk; p53; post-translational modification; protein-protein interaction; semiotic system..

Figure 1

Overview of p53 posttranslational modifications. The major domains of p53 and their distributions are depicted and only the modifications directly responsible for the listed effects are plotted. The modification sites within p53 are primarily updated from W Gu , .

Figure 2

Summary of the sequential interplay of modifications of p53. This figure shows the modification cascades which can be classified into short-range and long-range influences, which is reminiscent of the model raised by X-J Yang . In addition, effects on the downstream modification sites can be either negative (indicated by arrows with a '-' in a circle) or positive (indicated by arrows with a '+' in a circle). According to the sequential order of the modifications, they are crudely classified into two cassettes. Modifications in the initializing cassette are responsible for the sensing and distinguishing of the stresses and can transmit the signals to the functional cassette. Modification combinations in the functional cassette can induce specific biological outcome.

Figure 3

Generalization of the synergistic manner of different modifications and their binding partners. The functions of the p53 modifications are mutually dependent. A given combination of modifications can exert their specific functions simultaneously, and a specific binding partner, usually protein, mediates the function of modifications. Dashed lines and questions marks highlight that these modifications are likely to function synergistically.

Figure 4

Diagram of the p53 'code system'. At homeostasis, p53 is mainly presented in two forms: chromatin-bound (b) form and unbound form (c). Under stress, p53 is modified combinatorially by various enzymes. Thus, the 'code' is written (a). Specific 'code' on chromatin-bound p53 can recruit either histone modifying enzymes (d), histone remodelers (e) or other regulatory proteins (f) to the vicinity of the response element p53 is bound to. As for the unbound form, DNA with p53-binding sites (g) and other enzymes (h) recognize the code. Different 'readers' lead to distinct outcomes. Modifications of histones, remodeling of chromatin, directly activation or repression of transcription, conformational changes as well as extensive modifications of p53 are the effects of histone modifying enzymes, histone remodelers, additional regulatory proteins, specific DNA sequences and other enzymes, respectively.