Induction of cytoplasmic accumulation of p53: a mechanism for low levels of arsenic exposure to predispose cells for malignant transformation.
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.
Huang
Yelin
Y
Department of Genetics and Complex Disease, Harvard School of Public Health, Boston, Massachusetts, USA.
Zhang
Jianglin
J
McHenry
Kevin T
KT
Kim
Mihee M
MM
Zeng
Weiqi
W
Lopez-Pajares
Vanessa
V
Dibble
Christian C
CC
Mizgerd
Joseph P
JP
Yuan
Zhi-Min
ZM
D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D003593:Cytoplasm / Q000378:metabolism*; D004249:DNA Damage; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D048049:Extracellular Signal-Regulated MAP Kinases; D001151:Arsenic; D005472:Fluorouracil