title: Caspase-1 is a novel target of p63 in tumor suppression.
abstract: p63 is a p53 family transcription factor, which besides unique roles in epithelial development, shares tumor suppressive activity with its homolog p53. The p63 gene has different transcriptional start sites, which generate two N-terminal isoforms (transactivation domain (TA)p63 and amino terminal truncated protein(ΔN)p63); in addition alternative splicing at the 5'-end give rise to at least five C-terminal isoforms. This complexity of gene structure has probably fostered the debate and controversy on p63 function in cancer, with TP63-harboring two distinctive promoters, codifying for the TAp63 and ΔNp63 isoforms, and having discrete functions. However, ΔNp63 also drives expression of target genes that have a relevant role in cancer and metastasis. In this study, we identified a novel p63 transcriptional target, caspase-1. Caspase-1 is proinflammatory caspase, which functions in tumor suppression. We show that both p63 isoforms promote caspase-1 expression by physical binding to its promoter. Consistent with our in vitro findings, we also identified a direct correlation between p63 and caspase-1 expression in human cancer data sets. In addition, survival estimation analysis demonstrated that functional interaction between p63 and caspase-1 represents a predictor of positive survival outcome in human cancers. Overall, our data report a novel p63 target gene involved in tumor suppression, and the clinical analysis underlines the biological relevance of this finding and suggests a further clinically predictive biomarker.
authors.affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK.
authors.forename: I
authors.initials: I
authors.lastname: Celardo
authors.forename: F
authors.initials: F
authors.lastname: Grespi
authors.forename: A
authors.initials: A
authors.lastname: Antonov
authors.forename: F
authors.initials: F
authors.lastname: Bernassola
authors.forename: A V
authors.initials: AV
authors.lastname: Garabadgiu
authors.forename: G
authors.initials: G
authors.lastname: Melino
authors.forename: I
authors.initials: I
authors.lastname: Amelio
mesh_terms: D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D020170:Caspase 1