title: Human delta Np73 regulates a dominant negative feedback loop for TAp73 and p53.
abstract: Inactivation of the tumour suppressor p53 is the most common defect in cancer cells. p53 is a sequence specific transcription factor that is activated in response to various forms of genotoxic stress to induce cell cycle arrest and apoptosis. Induction of p53 is subjected to complex and strict control through several pathways, as it will often determine cellular fate. The p73 protein shares strong structural and functional similarities with p53 such as the potential to activate p53 responsive genes and the ability to induce apoptosis. In addition to alternative splicing at the carboxyl terminus which yields several p73 isoforms, a p73 variant lacking the N-terminal transactivation domain (Delta Np73) was described in mice. In this study, we report the cloning and characterisation of the human Delta Np73 isoforms, their regulation by p53 and their possible role in carcinogenesis. As in mice, human Delta Np73 lacks the transactivation domain and starts with an alternative exon (exon 3'). Its expression is driven by a second promoter located in a genomic region upstream of this exon, supporting the idea of two independently regulated proteins, derived from the same gene. As anticipated, Delta Np73 is capable of regulating TAp73 and p53 function since it is able to block their transactivation activity and their ability to induce apoptosis. Interestingly, expression of the Delta Np73 is strongly up-regulated by the TA isoforms and by p53, thus creating a feedback loop that tightly regulates the function of TAp73 and more importantly of p53. The regulation of Delta Np73 is exerted through a p53 responsive element located on the Delta N promoter. Expression of Delta Np73 not only regulates the function of p53 and TAp73 but also shuts off its own expression, once again finely regulating the whole system. Our data also suggest that increased expression of Delta Np73, functionally inactivating p53, could be involved in tumorogenesis. An extensive analysis of the expression pattern of Delta Np73 in primary tumours would clarify this issue.
authors.affiliation: Department of Clinical Research and Medical Oncology/Hematology, University and Inselspital, Berne, Switzerland.
authors.forename: T J
authors.initials: TJ
authors.lastname: Grob
authors.forename: U
authors.initials: U
authors.lastname: Novak
authors.forename: C
authors.initials: C
authors.lastname: Maisse
authors.forename: D
authors.initials: D
authors.lastname: Barcaroli
authors.forename: A U
authors.initials: AU
authors.lastname: Lüthi
authors.forename: F
authors.initials: F
authors.lastname: Pirnia
authors.forename: B
authors.initials: B
authors.lastname: Hügli
authors.forename: H U
authors.initials: HU
authors.lastname: Graber
authors.forename: V
authors.initials: V
authors.lastname: De Laurenzi
authors.forename: M F
authors.initials: MF
authors.lastname: Fey
authors.forename: G
authors.initials: G
authors.lastname: Melino
authors.forename: A
authors.initials: A
authors.lastname: Tobler
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019976:Cloning, Organism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D006801:Humans; D007438:Introns; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation / Q000235:genetics / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human; C454920:delta Np73, mouse; C022354:phosphoaminoacyl-tRNA synthetase phosphatase; D010749:Phosphoprotein Phosphatases