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Cadmium coordinates up-regulation of cytoprotective genes and protection agains metal toxicity by inhibiting the ubiquitination of Nrf2 and disrupting the Nrf2/Keap1 complex.

He-X; Lin-GX; Chen-MG; Ma-Q
Ubiquitin and signaling, Keystone Symposia on Molecular and Cellular Biology, February 4-9, 2007, Big Sky, Montana, 2007 Book of Abstracts. Schulman BA, Hunter T, Hochstrasser MW, Joazeiro CAP, eds. Silverthorne, CO: Keystone Symposia, 2007 Feb; :57
Transcription factor Nrf2 is a key regulator of genes encoding phase II detoxification enzymes and antioxidant proteins in response to environmental chemical insults. Under homeostatic conditions, Nrf2 is rapidly degradated through a Keap1-dependent, ubiquitin-26S proteasome pathway. Cadmium (Cd) is a major occupational/environmental toxic metal element and a proven human carcinogen. Exposure to Cd can cause a wide range of toxicity and disease in humans. The molecular mechanism of Cd action is currently unclear. We reported here that Cd induces cytoprotective genes NAD(P)H-quinone oxidoreductase I (Nq01) and heme oxygenase I (Ho-1) via the Nrf2/Keap1 pathway. Genetic experiments using mouse embryonic fibroblast (MEF) cells derived from wild type or Nrf2 knockout mice revealed that the cells lacking Nrf2 exhibited markedly increased production of ROS and sensitivity to Cd cytotoxicity. In MEF cells with wild type Nrf2 and mouse hepa 1c1c7 cells, Cd increased the Nrf2 protein level but not the Nrf2 mRNA level dose-dependently. Cd stabilized the Nrf2 protein by inhibiting the Keap1/CuI3dependent ubiquitination and 26S proteasomal turnover of Nrf2. Cd did not affect the protein levels of Keap1, which is a repressor of the cytoplasmic Nrf2, or Cul-3, an E3 ligase involved in the proteasomal degradation of Nrf2. Using cell fractionation and immunoprecipitation, we further demonstrated that Nrf2 and Keap1 were both detected in the cytoplasm and nucleus. Both proteins were ubiquitinated in the cytoplasm. Cd treatment reduced the ubiquitination of Nrf2, increased the nuclear accumulation of Nrf2, and disrupted the Nrf2/Keap1 complex in the nucleus. Chromatin immunoprecipitation (ChiP) assay revealed that Cd substantially increased the ARE occupancy of Nrf2 but not keap1, indicating Keap1 may recycle from the nucleus to the cytoplasm. These results provide a new model of Nrf2 activation by toxic metals.
Gene-mutation; Genotoxic-effects; Genotoxicity; Heavy-metals; Cell-biology; Cell-cultures; Metals
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Abstract; Conference/Symposia Proceedings
Schulman-BA; Hunter-T; Hochstrasser-MW; Joazeiro-CAP
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Ubiquitin and signaling, Keystone Symposia on Molecular and Cellular Biology, February 4-9, 2007, Big Sky, Montana, 2007 Book of Abstracts