title: Generation of DeltaTAp73 proteins by translation from a putative internal ribosome entry site.
abstract: p73 belongs to a family of transcription factors, including p53 and p63, that mediate response to DNA damage and cellular stress by inducing DNA repair, cell cycle arrest, and apoptosis. TP73 gene contains two promotors and several splice variants resulting in up to 24 possible permutations of p73 proteins which underlies the complexity of the family and its regulatory mechanisms. p73 variants lacking the N-terminal, denoted as DeltaTAp73, are not transcriptionally competent and they act in a dominant negative fashion over TAp73. DeltaTAp73 isoforms can be generated by alternative promotor usage, giving rise to DeltaNp73, or alternative splicing of exons 2, 3 or 2, and 3 together. Such transcript isoforms potentially produce oncogenic proteins and they were shown to be present in primary tumors and tumor-derived cell lines. We investigated the possibility of additional mechanisms by which p73 protein could be regulated and discovered a putative internal ribosome entry site (IRES) in exon 2. Translation initiation of TAp73 mRNA results in a DeltaNp73-like peptide, thus demonstrating an additional mechanism whereby a DeltaTA p73 protein is produced from a transcript originally generated from the P1 promotor of the p73 gene.
authors.affiliation: Medical Research Council Toxicology Unit, Hodgkin Building, Lancaster Road, University of Leicester, Leicester, LE1 9HN United Kingdom.
authors.forename: A Emre
authors.initials: AE
authors.lastname: Sayan
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Roperch
authors.forename: Berna S
authors.initials: BS
authors.lastname: Sayan
authors.forename: Mario
authors.initials: M
authors.lastname: Rossi
authors.forename: M J
authors.initials: MJ
authors.lastname: Pinkoski
authors.forename: Richard A
authors.initials: RA
authors.lastname: Knight
authors.forename: Anne E
authors.initials: AE
authors.lastname: Willis
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D005822:Genetic Vectors; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics; D012270:Ribosomes / Q000235:genetics* / Q000378:metabolism*; D017384:Sequence Deletion; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins