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Molecular and Cellular Biology, August 2004, p. 6645-6652, Vol. 24, No. 15
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.15.6645-6652.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Vitamin C Is a Kinase Inhibitor: Dehydroascorbic Acid Inhibits IB Kinase ß

Department of Clinical Laboratories,¹ Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center,² Structural Biology Program, Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York, New York³

Received 3 February 2004/ Returned for modification 9 March 2004/ Accepted 10 May 2004

Reactive oxygen species (ROS) are key intermediates in cellular signal transduction pathways whose function may be counterbalanced by antioxidants. Acting as an antioxidant, ascorbic acid (AA) donates two electrons and becomes oxidized to dehydroascorbic acid (DHA). We discovered that DHA directly inhibits IB kinase ß (IKKß) and IKK enzymatic activity in vitro, whereas AA did not have this effect. When cells were loaded with AA and induced to generate DHA by oxidative stress in cells expressing a constitutive active IKKß, NF-B activation was inhibited. Our results identify a dual molecular action of vitamin C in signal transduction and provide a direct linkage between the redox state of vitamin C and NF-B signaling events. AA quenches ROS intermediates involved in the activation of NF-B and is oxidized to DHA, which directly inhibits IKKß and IKK enzymatic activity. These findings define a function for vitamin C in signal transduction other than as an antioxidant and mechanistically illuminate how vitamin C down-modulates NF-B signaling.

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