The role of hydroxyl radical as a messenger in Cr(VI)-induced p53 activation.
The present study investigates whether reactive oxygen species (ROS) are involved in p53 activation, and if they are, which species is responsible for the activation. Our hypothesis is that hydroxyl radical (.OH) functions as a messenger for the activation of this tumor suppressor protein. Human lung epithelial cells (A549) were used to test this hypothesis. Cr(VI) was employed as the source of ROS due to its ability to generate a whole spectrum of ROS inside the cell. Cr(VI) is able to activate p53 by increasing the protein levels and enhancing both the DNA binding activity and transactivation ability of the protein. Increased cellular levels of superoxide radicals (O(2)(-).), hydrogen peroxide (H(2)O(2)), and.OH radicals were detected on the addition of Cr(VI) to the cells. Superoxide dismutase, by enhancing the production of H(2)O(2) from O(2)(-). radicals, increased p53 activity. Catalase, an H(2)O(2) scavenger, eliminated.OH radical generation and inhibited p53 activation. Sodium formate and aspirin,.OH radical scavengers, also suppressed p53 activation. Deferoxamine, a metal chelator, inhibited p53 activation by chelating Cr(V) to make it incapable of generating radicals from H(2)O(2). NADPH, which accelerated the one-electron reduction of Cr(VI) to Cr(V) and increased.OH radical generation, dramatically enhanced p53 activation. Thus.OH radical generated from Cr(VI) reduction in A549 cells is responsible for Cr(VI)-induced p53 activation.
Wang
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Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown 26505, West Virginia, USA.
Leonard
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Ye
J
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Ding
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Shi
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D002274:Carcinogens, Environmental / Q000494:pharmacology*; D002460:Cell Line; D002857:Chromium / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism*; D010101:Oxygen Consumption; D015290:Second Messenger Systems / Q000502:physiology*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D002274:Carcinogens, Environmental; D005609:Free Radicals; D016159:Tumor Suppressor Protein p53; D002857:Chromium; C074702:chromium hexavalent ion; D017665:Hydroxyl Radical