p53 and its isoforms in cancer

Abstract

p53, p63 and p73 are members of the p53 gene family involved in development, differentiation and response to cellular stress. p53 gene is a transcription factor essential for the prevention of cancer formation. The p53 pathway is ubiquitously lost in human cancer either by p53 gene mutation (60% of cancers) or by lost of cell signalling upstream and downstream of p53 in the remaining cancers expressing WTp53 gene. As p53 pathway inactivation is a common denominator to all cancers, the understanding of p53 tumour suppressor activity is likely to bring us closer to cancer therapy. However, despite all the experimental evidences showing the importance of p53 in preventing carcinogenesis, it is difficult in clinical studies to link p53 status to cancer treatment and clinical outcome. The recent discovery that p53 gene encodes for nine different p53 proteins (isoforms) may have a profound impact on our understanding of p53 tumour suppressor activity. Studies in several tumour types have shown that the nine different p53 isoforms are abnormally expressed in tumour tissues compared to normal cells. p53 protein isoforms modulate p53 transcriptional activity and cell fate outcome in response to stress. Regulation of p53 function in normal and tumour tissues in man is likely to be more complex than has been hitherto appreciated. Therefore, the tumour p53 status needs to be determined more accurately by integrating p53 isoform expression, functional p53 mutation analysis and a panel of antibodies specific of p53 and of its target genes.

Figure 1

Human p63. (A) Schema of the human p63 gene structure: alternative splicing (α, β, γ) and alternative promoters (P1 and P2) are indicated. (B) p63 protein isoforms: TAp63 proteins encoded from promoter P1 contain the conserved N-terminal domain (FxxψW) of transactivation (TA). ΔNp63 proteins encoded from promoter P2 are amino-truncated proteins containing an N-terminal domain different from TAp63 proteins. Numbers indicate the exons encoding p63 protein isoforms.

Figure 2

Human p73. (A) Schema of the human p73 gene structure: alternative splicing (α, β, γ, ζ, Δ, ε, η) and alternative promoters (P1 and P2) are indicated. (B) p73 protein isoforms: TAp73 proteins encoded from promoter P1 contain the conserved N-terminal domain (FxxψW) of transactivation (TA). Ex2p73 proteins are due to alternative splicing of exon 2. They have lost the conserved N-terminal domain (FxxψW) of transactivation (TA), but still contain part of the transactivation domain (Exon-3). Ex2/3p73 proteins are due to alternative splicing of exons 2 and 3. They have entirely lost the TA domain and are initiated from exon 4. To our knowledge, the protein encoded by ΔN'p73 mRNA has not been described. ΔN'p73 variant is often overexpressed at the mRNA level in tumours. ΔN'p73 is due to alternative splicing of exon 3′ contained in intron 3. Theoretically, ΔN'p73 mRNA would encode either for a short p73 protein or p73 protein isoforms identical to ΔNp73. ΔN'p73 mRNA contains the normal initiation site of translation in exon 2 (ATG in perfect kozak sequence) and a stop codon in exon-3′. Therefore, it could encode for a short p73 protein composed only of the transactivation domain (FxxψW). It is possible that translation of ΔN'p73 mRNA is initiated from the third ATG available present in exon 3′and leading to p73 protein identical to ΔNp73 protein isoforms. ΔNp73 proteins encoded from promoter P2 are amino-truncated proteins containing an N-terminal domain different from TAp73 proteins. Numbers indicate the exons encoding p73 protein isoforms.

Figure 3

Human p53. (A) Schema of the human p53 gene structure: Alternative splicing (α, β, γ) and alternative promoters (P1, P1′ and P2) are indicated. p53 protein isoforms: (B) p53, p53β and p53γ proteins encoded from P1 or P1′ promoters contain the conserved N-terminal domain (FxxψW) of transactivation (TA). Δ133p53 isoforms encoded from promoter P2 are amino-truncated proteins deleted of the entire TA domain and deleted of part of the DNA-binding domain. Translation is initiated at ATG-133. Δ40p53 protein isoforms encoded from P1 or P1′ promoters are amino-truncated proteins due to alternative splicing of exon 2 and/or alternative initiation of translation at ATG-40). Δ40p53 protein isoform have lost the conserved N-terminal domain of transactivation (FxxψW), but still contain part of the transactivation domain. Δp53 protein isoform is due to noncanonical alternative splicing between the exon 7 and 9. Δp53 has lost 66 residues including the highly conserved domain V of the DNA-binding domain. The isoforms Δp53β, Δp53γ, Δ40Δp53, Δ40Δp53β, Δ40Δp53γ, Δ133Δp53, Δ133Δp53β and Δ133Δp53γ should theoretically be generated.