Vitamin C is a kinase inhibitor:: Dehydroascorbic acid inhibits IκBα kinase β
Vitamin C is a kinase inhibitor:: Dehydroascorbic acid inhibits IκBα kinase β
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DOI：
10.1128/mcb.24.15.6645-6652.2004
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发表时间：
2004-08-01
影响因子：
5.3
通讯作者：
Golde, DW
中科院分区：
文献类型：
--
作者：
Cárcamo, JM;Pedraza, A;Golde, DW
活性氧（ROS）是细胞信号转导途径中的关键中间体，其功能可以通过抗氧化剂来平衡。作为抗氧化剂，抗坏血酸（AA）提供两个电子并被氧化为脱氢抗坏血酸（DHA）。我们发现，在体外，α-氨基丁酸直接抑制IKK β和IKK α的酶活性，而AA没有这种作用。当细胞加载AA并在表达组成性活性IKK β的细胞中通过氧化应激诱导产生TNF时，NF-κ B活化被抑制。我们的研究结果确定了维生素C在信号转导中的双重分子作用，并提供了维生素C的氧化还原状态和NF-κ B信号转导事件之间的直接联系。AA淬灭参与NF-κ B活化的ROS中间体，并氧化为DHA，后者直接抑制IKK β和IKK α酶活性。这些发现定义了维生素C在信号转导中的功能，而不是作为抗氧化剂，并从机制上阐明了维生素C如何下调NF-κ B信号转导。
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 DRA directly inhibits IkappaBalpha kinase beta (IKKbeta) and IKKalpha enzymatic activity in vitro, whereas AA did not have this effect. When cells were loaded with AA and induced to generate DRA by oxidative stress in cells expressing a constitutive active IKKbeta, NF-kappaB 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-kappaB signaling events. AA quenches ROS intermediates involved in the activation of NF-kappaB and is oxidized to DHA, which directly inhibits IKKbeta and IKKalpha 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-kappaB signaling.