p53 Family: Role of Protein Isoforms in Human Cancer

Abstract

TP53, TP63, and TP73 genes comprise the p53 family. Each gene produces protein isoforms through multiple mechanisms including extensive alternative mRNA splicing. Accumulating evidence shows that these isoforms play a critical role in the regulation of many biological processes in normal cells. Their abnormal expression contributes to tumorigenesis and has a profound effect on tumor response to curative therapy. This paper is an overview of isoform diversity in the p53 family and its role in cancer.

Figure 1

Architectures of human TP53, TP73, and TP63 genes. (A) TP53, TP73, and TP63 genes encode the transactivation (TAD), DNA-binding (DBD), and oligomerization (OD) domains. TP73 and TP63 encode additional SAM (Sterile Alpha Motif) domain. Percentage homology of residues between p53, p63, and p73 is shown [11]. (B) TP53, TP63, and TP73 genes have two promoters (P1 and P2). The P1 promoters produce transactivation-competent full-length proteins (TA) while the P2 promoters produce TAD-deficient proteins (ΔN) with dominant-negative functions. p53 gene transcription is initiated from two distinct sites (P1 and P1′).

Figure 2

Interactions of p53 family isoforms. N-terminally truncated isoforms of p53, p73, and p63 play a dominant-negative role inhibiting transcriptional and other biological activities of TA isoforms.

Figure 3

An increased diversity of alternatively spliced species of p73 in colon adenocarcinoma. p73 gene transcription was analyzed in 10 colon tumors and normal colonic mucosa by RT-PCR. Normal specimen 2 represents 14 pooled normal samples. For details, see Vilgelm et al. [15].