title: Physical interaction with human tumor-derived p53 mutants inhibits p63 activities.
abstract: The p53 tumor suppressor gene is the most frequent target for genetic alterations in human cancers, whereas the recently discovered homologues p73 and p63 are rarely mutated. We and others have previously reported that human tumor-derived p53 mutants can engage in a physical association with different isoforms of p73, inhibiting their transcriptional activity. Here, we report that human tumor-derived p53 mutants can associate in vitro and in vivo with p63 through their respective core domains. We show that the interaction with mutant p53 impairs in vitro and in vivo sequence-specific DNA binding of p63 and consequently affects its transcriptional activity. We also report that in cells carrying endogenous mutant p53, such as T47D cells, p63 is unable to recruit some of its target gene promoters. Unlike wild-type p53, the binding to specific p53 mutants markedly counteracts p63-induced growth inhibition. This effect is, at least partially, mediated by the core domain of mutant p53. Thus, inactivation of p53 family members may contribute to the biological properties of specific p53 mutants in promoting tumorigenesis and in conferring selective survival advantage to cancer cells.
authors.affiliation: Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, Rome 00158, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Strano
authors.forename: Giulia
authors.initials: G
authors.lastname: Fontemaggi
authors.forename: Antonio
authors.initials: A
authors.lastname: Costanzo
authors.forename: Maria Giulia
authors.initials: MG
authors.lastname: Rizzo
authors.forename: Olimpia
authors.initials: O
authors.lastname: Monti
authors.forename: Alessia
authors.initials: A
authors.lastname: Baccarini
authors.forename: Giannino
authors.initials: G
authors.lastname: Del Sal
authors.forename: Massimo
authors.initials: M
authors.lastname: Levrero
authors.forename: Ada
authors.initials: A
authors.lastname: Sacchi
authors.forename: Moshe
authors.initials: M
authors.lastname: Oren
authors.forename: Giovanni
authors.initials: G
authors.lastname: Blandino
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000378:metabolism; D017931:DNA Primers; D004268:DNA-Binding Proteins; D016147:Genes, Tumor Suppressor; D006639:Histidine / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins; D009154:Mutation; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014157:Transcription Factors; D014364:Tryptophan / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
chemical_list: C081876:CKAP4 protein, human; D017931:DNA Primers; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D006639:Histidine; D014364:Tryptophan; D004247:DNA