Induction of cytoplasmic accumulation of p53: a mechanism for low levels of arsenic exposure to predispose cells for malignant transformation.
Induction of cytoplasmic accumulation of p53: a mechanism for low levels of arsenic exposure to predispose cells for malignant transformation.
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DOI：
10.1158/0008-5472.can-08-3025
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发表时间：
2008-11-15
期刊：
影响因子：
11.2
通讯作者：
Yuan ZM
中科院分区：
文献类型：
--
作者：
Huang Y;Zhang J;McHenry KT;Kim MM;Zeng W;Lopez-Pajares V;Dibble CC;Mizgerd JP;Yuan ZM
尽管流行病学研究已经将砷暴露与人类癌症的发展联系起来，但砷致瘤作用的潜在机制在很大程度上仍不明确。我们在这里报告，在接近环境暴露浓度的亚砷酸钠处理细胞与Hdm 2的上调和细胞质中p53的积累有关。通过丝裂原活化蛋白激酶途径，亚砷酸盐刺激P2启动子介导的Hdm 2表达，从而促进p53核输出。因此，p53对遗传毒性应激的反应受到损害，如响应于UV照射或5FU处理的受损的p53活化和凋亡所证明的。当用含亚砷酸盐的水喂养小鼠时，通过对5FU处理的显著钝化的p53依赖性组织应答进一步证明亚砷酸盐阻碍p53活化的能力。总之，我们的数据表明，砷化合物通过上调Hdm 2和随后的p53失活使细胞易于恶性转化。
Although epidemiologic studies have linked arsenic exposure to the development of human cancer, the mechanisms underlying the tumorigenic role of arsenic remain largely undefined. We report here that treatment of cells with sodium arsenite at the concentrations close to environmental exposure is associated with the up-regulation of Hdm2 and the accumulation of p53 in the cytoplasm. Through the mitogen-activated protein kinase pathway, arsenite stimulates the P2 promoter–mediated expression of Hdm2, which then promotes p53 nuclear export. As a consequence, the p53 response to genotoxic stress is compromised, as evidenced by the impaired p53 activation and apoptosis in response to UV irradiation or 5FU treatment. The ability of arsenite to impede p53 activation is further demonstrated by a significantly blunted p53-dependent tissue response to 5FU treatment when mice were fed with arsenite-containing water. Together, our data suggests that arsenic compounds predispose cells to malignant transformation by up-regulation of Hdm2 and subsequent p53 inactivation.