Huang Yelin, Zhang Jianglin, McHenry Kevin T, Kim Mihee M, Zeng Weiqi, Lopez-Pajares Vanessa, Dibble Christian C, Mizgerd Joseph P, Yuan Zhi-Min
Department of Genetics and Complex Disease, Harvard School of Public Health, Boston, Massachusetts, USA.
Cancer Res. 2008 Nov 15;68(22):9131-6. doi: 10.1158/0008-5472.CAN-08-3025.
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.
尽管流行病学研究已将砷暴露与人类癌症的发生联系起来，但砷致癌作用的潜在机制仍 largely 未明确。我们在此报告，用接近环境暴露浓度的亚砷酸钠处理细胞，与 Hdm2 的上调以及 p53 在细胞质中的积累有关。通过丝裂原活化蛋白激酶途径，亚砷酸盐刺激 Hdm2 的 P2 启动子介导的表达，进而促进 p53 的核输出。结果，p53 对基因毒性应激的反应受到损害，这在对紫外线照射或 5FU 处理的 p53 激活和凋亡受损中得到证明。当给小鼠饮用含砷水时，p53 依赖性组织对 5FU 处理的反应明显减弱，进一步证明了亚砷酸盐阻碍 p53 激活的能力。总之，我们的数据表明，砷化合物通过上调 Hdm2 和随后的 p53 失活使细胞易于发生恶性转化。
