A novel mechanism of tumorigenesis involving pH- dependent destabilization of a mutant p53 tetramer
A novel mechanism of tumorigenesis involving pH- dependent destabilization of a mutant p53 tetramer
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DOI：
10.1038/nsb730
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发表时间：
2002-01-01
期刊：
影响因子：
--
通讯作者：
Kriwacki, RW
中科院分区：
文献类型：
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作者：
DiGiammarino, EL;Lee, AS;Kriwacki, RW
p53肿瘤抑制因子需要四聚化以作为细胞周期停滞和/或细胞凋亡的引发剂起作用。巴西南部儿童肾上腺皮质癌（ACC）的发病率升高，在p53的四聚化结构域（p53-R337 H; 36例患者中的35例）中存在Arg 337至His突变。突变体四聚化结构域（p53 tet-R337 H）采用天然样折叠，但不如野生型结构域（p53 tet-wt）稳定。此外，p53 tet-R337 H的稳定性在生理范围内对pH高度敏感;这种敏感性与突变的His 337的质子化状态相关。这些结果表明，pH敏感的p53（R337 H）的分子缺陷，表明pH依赖性p53功能障碍是这些情况下的ACC在巴西儿童的分子基础。
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.