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Nat Struct Biol. 2002 Jan;9(1):12-6.

A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer.

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Department of Structural Biology, St. Jude Children's Research Hospital, 332 N. Lauderdale St., Memphis, Tennessee 38105, USA.


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.

[Indexed for MEDLINE]

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