title: A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer.
abstract: The p53 tumor suppressor requires tetramerization to function as an initiator of cell cycle arrest and/or apoptosis. Children in southern Brazil that exhibit an elevated incidence of adrenocortical carcinoma (ACC) harbor an Arg 337 to His mutation within the tetramerization domain of p53 (p53-R337H; 35 of 36 patients). The mutant tetramerization domain (p53tet-R337H) adopts a native-like fold but is less stable than the wild type domain (p53tet-wt). Furthermore, the stability of p53tet-R337H is highly sensitive to pH in the physiological range; this sensitivity correlates with the protonation state of the mutated His 337. These results demonstrate a pH-sensitive molecular defect of p53 (R337H), suggesting that pH-dependent p53 dysfunction is the molecular basis for these cases of ACC in Brazilian children.
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, 332 N. Lauderdale St., Memphis, Tennessee 38105, USA.
authors.forename: Enrico L
authors.initials: EL
authors.lastname: DiGiammarino
authors.forename: Amanda S
authors.initials: AS
authors.lastname: Lee
authors.forename: Craig
authors.initials: C
authors.lastname: Cadwell
authors.forename: Weixing
authors.initials: W
authors.lastname: Zhang
authors.forename: Brian
authors.initials: B
authors.lastname: Bothner
authors.forename: Raul C
authors.initials: RC
authors.lastname: Ribeiro
authors.forename: Gerard
authors.initials: G
authors.lastname: Zambetti
authors.forename: Richard W
authors.initials: RW
authors.lastname: Kriwacki
mesh_terms: D018268:Adrenocortical Carcinoma / Q000737:chemistry / Q000453:epidemiology / Q000235:genetics*; D000595:Amino Acid Sequence; D001938:Brazil / Q000453:epidemiology; D002648:Child; D002850:Chromatography, Gel; D002942:Circular Dichroism; D006639:Histidine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D011522:Protons; D055672:Static Electricity; D013696:Temperature; D013816:Thermodynamics; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D011522:Protons; D016159:Tumor Suppressor Protein p53; D006639:Histidine