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. 1. Introduction Alternative splicing allows a single gene to express multiple protein variants. It is estimated that 92–95% of human multiexon genes undergo alternative splicing [1, 2]. Abnormal alterations of splicing may interfere with normal cellular homeostasis and lead to cancer development [3–5]. The p53 protein family is comprised of three transcription factors: p53, p63, and p73. Phylogenetic analysis revealed that this family originated from a p63/73-like ancestral gene early in metazoan evolution [6, 7]. Maintenance of genetic stability of germ cells seems to be its ancestral function [8]. The p53 family regulates many vital biological processes, including cell differentiation, proliferation, and cell death/apoptosis [9, 10]. Dysregulation of the p53 family plays a critical role in tumorigenesis and significantly affects tumor response to therapy. This review summarizes current data on the regulation of p53, p63, and p73 isoforms and their roles in cancer. 2. Structure and Function p53, p63, and p73 genes are located on chromosomes 17p13.1, 3q27-29, and 1p36.2-3, respectively. These genes encode proteins with similar domain structures and significant amino acid sequence homology in the transactivation, DNA-binding and oligomerization domains (Figure 1). The highest amino acid identity is in the DNA-binding domain (~60%). Evolutionally, this domain is the most conserved, suggesting that regulation of transcription plays a pivotal role in an array of functions attributed to the p53 family. Less similarity is found in the oligomerization and transactivation domains (~30%). 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
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