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RESEARCH PAPER
Department of Surgery and Department of Molecular Oncology, Cancer Research-UK Cell Transformation Research Group, University of Dundee, Ninewells Hospital, Dundee, Scotland DD1 9SY, United Kingdom
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 p53
can bind differentially to promoters and can enhance p53 target gene expression in a promoter-dependent manner, while 
133p53 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.
[Keywords: Splice; promoter; Drosophila; cancer; p73; p63]
Received June 3, 2005; revised version accepted July 20, 2005.
Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1339905.
3 E-MAIL j.bourdon{at}dundee.ac.uk; FAX 44-1382-496361.
1 Present address: IMCB, 61 Biopolis Drive, Singapore 138673.
2 E-MAIL d.p.lane{at}dundee.ac.uk; FAX 44-1382-496361.
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