The p53 family and programmed cell death

Abstract

The p53 tumor suppressor continues to hold distinction as the most frequently mutated gene in human cancer. The ability of p53 to induce programmed cell death, or apoptosis, of cells exposed to environmental or oncogenic stress constitutes a major pathway whereby p53 exerts its tumor suppressor function. In the past decade, we have discovered that p53 is not alone in its mission to destroy damaged or aberrantly proliferating cells: it has two homologs, p63 and p73, that in various cellular contexts and stresses contribute to this process. In this review, the mechanisms whereby p53, and in some cases p63 and p73, induce apoptosis are discussed. Other reviews have focused more extensively on the contribution of individual p53-regulated genes to apoptosis induction by this protein, whereas in this review, we focus more on those factors that mediate the decision between growth arrest and apoptosis by p53, p63 and p73, and on the post-translational modifications and protein-protein interactions that influence this decision.

Figure 1. p53 family member isoforms

Schematic presentation of p53, p63, and p73 isoforms. Approximate location of the transactivation (TA) domain, proline rich domain (PR), DNA binding domain (DBD), oligomerization domain (OD) and the sterile alpha motif (SAM) are indicated. The amino acid identity between the TA, DBD, and OD of p53 and p63/p73 as well as between p63 and p73 is denoted. Full length (FL) p53 or TAp63 and TAp73 protein are transcribed from a promoter located in the non-coding region of exon 1 (P1 promoter) of the p53, p63, and p73 gene. Δ133p53, ΔNp63, and ΔNp73 isoforms are generated by transcription from a promoter (P2 promoter) located in intron 3 of the p63 and p73 gene or intron 4 of the p53 gene. Further ΔN variants are generated by alternative splicing of the N-terminus (Δ40p53, Δex2p73, Δex2/3p73). Alternative splicing of the C-terminal region yields additional variants for p53 (FL, β, & γ), p63 (α, β, & γ), and p73(α, β, γ, δ, ε, ζ, η, & θ). p53 β and γ lack the oligomerization domain.

Figure 2. Upstream mediators of p53 and p73-dependent cell death