title: P66Shc-rac1 pathway-mediated ROS production and cell migration is downregulated by ascorbic acid.
abstract: The oxidative role(s) of p66Shc protein has been increasingly expanded over the last decade. However, its relation with the most potent antioxidant molecule, i.e. ascorbic acid has never been studied. We have previously shown that p66Shc mediates rac1 activation, reactive oxygen species (ROS) production and cell death. Here we studied the effect of ascorbic acid on the pathway involving p66Shc and rac1. Our results indicate a decrease in the expression of p66Shc in a dose- and time-dependent manner. We studied the effect of ascorbic acid on rac1 expression and its activity. Ascorbic acid has no effect on total rac1 expression; however, rac1 activation was inhibited in a dose-dependent manner. Results suggest that the decrease in rac1 activity is mediated through ascorbic acid-modulated p66Shc expression. The decrease in rac1 activity was evident in cells transfected with the p66shc mutant (proline motif mutant, at residues P47 to P50). Our studies indicate that p66Shc-mediated ROS upregulation is significantly decreased in the presence of ascorbic acid. Cell migration experiments point towards the inhibition of p66Shc-rac1-mediated migration in the presence of ascorbic acid. Finally, results are suggestive that ascorbic acid-mediated decrease in Shc expression occurs through an increased Shc ubiquitination. Overall, the study brings out the novel role of ascorbic acid in antioxidant signal transduction.
authors: Department of Biotechnology, University of Kashmir, Jammu and Kashmir, India.
authors: Deeba
authors: D
authors: Kirmani
authors: Hina F
authors: HF
authors: Bhat
authors: Muneesa
authors: M
authors: Bashir
authors: Mohammad A
authors: MA
authors: Zargar
authors: Firdous A
authors: FA
authors: Khanday
mesh_terms: D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001205:Ascorbic Acid / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D006801:Humans; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D054875:Ubiquitination / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000975:Antioxidants; C107953:RAC1 protein, human; D017382:Reactive Oxygen Species; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D020830:rac1 GTP-Binding Protein; D001205:Ascorbic Acid