Herbimycin A abrogates nuclear factor-kappaB activation by interacting preferentially with the IkappaB kinase beta subunit.
Herbimycin A abrogates nuclear factor-kappaB activation by interacting preferentially with the IkappaB kinase beta subunit.
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DOI：
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发表时间：
2004
影响因子：
3.6
通讯作者：
S. Ogino;K. Tsuruma;T. Uehara;Y. Nomura
中科院分区：
文献类型：
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作者：
S. Ogino;K. Tsuruma;T. Uehara;Y. Nomura
核因子-kappaB是炎症反应中的关键转录因子。我们已经报道了一种有效的Src酪氨酸激酶抑制剂Herbimycin A，它可以减弱由细胞因子、细菌内毒素和过氧化氢触发的NF-kappaB激活。在被该药物抑制的同时，神经胶质细胞中依赖于核因子-kappaB的基因表达，如细胞因子、趋化因子和诱导型一氧化氮，也被特异性地抑制。在本研究中，我们试图阐明除草霉素A在这一途径上可能的靶蛋白。我们在这里证明了除草剂A优先抑制IKK(IkappaB激酶)β。此外，用丙氨酸取代IKKβ中59位半胱氨酸(Cys59)导致对除草剂A不敏感，提示该化合物可能与位于催化ATP结合位点附近的Cys59残基相互作用。综上所述，这些结果表明，除草霉素A可以通过对IKKβ的特异性抑制而被认为是一种新的抗炎药物候选药物，从而阻止参与炎症反应发病机制的NF-kappaB依赖基因的表达。
NF (nuclear factor)-kappaB is known to be a critical transcription factor in inflammatory responses. We have reported that herbimycin A, a potent Src tyrosine kinase inhibitor, attenuates the NF-kappaB activation triggered by cytokines, bacterial endotoxin, and hydrogen peroxide. Accompanying the suppression by this agent, NF-kappaB-dependent gene expressions, such as cytokine, chemokine, and inducible-type nitric oxide, are specifically inhibited in glial cells. In the present study, we attempted to elucidate the possible target protein for herbimycin A on this pathway. We demonstrate here that herbimycin A preferentially inhibits IKK (IkappaB kinase)beta. Furthermore, substituting alanine for the cysteine at 59 (Cys59) in IKKbeta resulted in the insensitivity to herbimycin A, suggesting that this compound may interact with the Cys59 residue located near the catalytic ATP binding site. Taken together, these results indicate that herbimycin A can be considered a novel candidate for an anti-inflammatory drug agent through its specific inhibition of IKKbeta, which results in prevention of the expression of NF-kappaB-dependent genes implicated in the pathogenesis of inflammatory responses.