p53 isoforms can regulate p53 transcriptional activity

TLDR

The p53 family genes p73 and p63 are known to have multiple splice variants and alternative promoters, but such diversity had not been reported for p53 until this study, highlighting the need to understand p53 isoform expression in normal and tumor tissues. The study demonstrates that p53 possesses an evolutionarily conserved alternative promoter that generates multiple splice variants expressed in a tissue‑dependent manner, with p53β enhancing target gene transcription and Δ133p53 acting as a dominant‑negative inhibitor of apoptosis, and shows differential expression of these isoforms in breast tumors versus normal tissue.

Abstract

The recently discovered p53-related genes, p73 and p63, express multiple splice variants and N-terminally truncated forms initiated from an alternative promoter in intron 3. To date, no alternative promoter and multiple splice variants have been described for the p53 gene. In this study, we show that p53 has a gene structure similar to the p73 and p63 genes. The human p53 gene contains an alternative promoter and transcribes multiple splice variants. We show that p53 variants are expressed in normal human tissue in a tissue-dependent manner. We determine that the alternative promoter is conserved through evolution from Drosophila to man, suggesting that the p53 family gene structure plays an essential role in the multiple activities of the p53 family members. Consistent with this hypothesis, p53 variants are differentially expressed in human breast tumors compared with normal breast tissue. We establish that p53β can bind differentially to promoters and can enhance p53 target gene expression in a promoter-dependent manner, while Δ133p53 is dominant-negative toward full-length p53, inhibiting p53-mediated apoptosis. The differential expression of the p53 isoforms in human tumors may explain the difficulties in linking p53 status to the biological properties and drug sensitivity of human cancer.