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

被引：196

作者：

DiGiammarino, EL

Lee, AS

Cadwell, C

Zhang, WX

Bothner, B

Ribeiro, RC

Zambetti, G

Kriwacki, RW

机构：

[1] St Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA

[2] St Jude Childrens Res Hosp, Dept Biochem, Memphis, TN 38105 USA

[3] Univ Tennessee, Ctr Hlth Sci, Dept Mol Sci, Memphis, TN 38163 USA

[4] St Jude Childrens Res Hosp, Int Outreach Program, Memphis, TN 38105 USA

[5] St Jude Childrens Res Hosp, Dept Hematol Oncol, Memphis, TN 38105 USA

来源：

NATURE STRUCTURAL BIOLOGY | 2002年 / 9卷 / 01期

关键词：

D O I：

10.1038/nsb730

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：12 / 16

页数：5

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[21] Proliferation and apoptosis in the human adrenal cortex during the fetal and perinatal periods: Implications for growth and remodeling [J].