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Induction of Cytoplasmic Accumulation of p53: A Mechanism for Low Levels of Arsenic Exposure to Predispose Cells for Malignant Transformation

Departments of ¹ Genetics and Complex Disease, and ² Environmental Health, Harvard School of Public Health, Boston, Massachusetts; and ³ Department of Radiation Oncology, University of Texas Health Science Center at San Antonio, San Antonio, Texas

Requests for reprints: Zhi-Min Yuan, Department of Radiation Oncology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229. Phone: 210-562-9144; Fax: 210-562-9157; E-mail: yuanz{at}uthscsa.edu.

Key Words: the p53 response • low level of arsenic exposure

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. [Cancer Res 2008;68(22):9131–6]

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