Deficiency of NRH:Quinone oxidoreductase 2 differentially regulates TNF signaling in keratinocytes:: Up-regulation of apoptosis correlates with down-regulation of cell survival kinases
Deficiency of NRH:Quinone oxidoreductase 2 differentially regulates TNF signaling in keratinocytes:: Up-regulation of apoptosis correlates with down-regulation of cell survival kinases
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DOI：
10.1158/0008-5472.can-07-2213
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发表时间：
2007-10-15
期刊：
影响因子：
11.2
通讯作者：
Aggarwal, Bharat B.
中科院分区：
文献类型：
--
作者：
Ahn, Kwang Seok;Gong, Xing;Aggarwal, Bharat B.
NRH：醌氧化还原酶2（NQO 2）是一种细胞溶质黄素蛋白，催化醌和醌类化合物的双电子还原为氢醌。虽然一个同系物，NAD（P）H：醌氧化还原酶1（NQO 1）的作用，是很好地定义在氧化应激，肿瘤，和致癌作用，很少有人知道NQO 2在这些细胞反应的作用机制。使用来自野生型和NQO 2敲除（NQO 2（-/-））小鼠的角质形成细胞研究NQO 2是否在肿瘤坏死因子（TNF）信号传导中具有任何作用。尽管野生型细胞暴露于TNF导致核因子-κ B（NF-κ B）和I κ B α激酶活化、I κ B α降解、p65磷酸化和p65核转位，但这种细胞因子对NQO 2（-/-）细胞没有影响。NQO 2的缺失也消除了TNF诱导的c-jun NH 2-末端激酶、Akt、p38和p44/p42丝裂原活化蛋白激酶的激活。在NQO 2（-/-）细胞中，TNF对各种抗凋亡基因产物（NIMP-9、细胞周期蛋白D1、考克斯-2、IAP 1、LAP 2、Bcl-2、cFLIP和XIAP）的诱导也被消除。这与增强TNF诱导的细胞凋亡相关，如细胞活力、膜联蛋白V染色和半胱天冬酶激活所示。与此一致，我们还发现TNF激活NQO 2，NQO 2特异性小干扰RNA消除TNF诱导的NQO 2活性和NF-κ B激活。总之，我们的研究结果表明，NQO 2的缺失在TNF信号通路中起着不同的作用：通过抑制细胞存活信号和增强TNF诱导的凋亡。
NRH:quinone oxidoreductase 2 (NQO2) is a cytosolic flavoprotein that catalyzes the two-electron reduction of quinones and quinoid compounds to hydroquinones. Although the role of a homologue, NAD(P)H:quinone oxidoreductase 1 (NQO1), is well defined in oxidative stress, neoplasia, and carcinogenesis, little is known about the mechanism of actions of NQO2 in these cellular responses. Whether NQO2 has any role in tumor necrosis factor (TNF) signaling was investigated using keratinocytes derived from wild-type and NQO2 knockout (NQO2(-/-)) mice. Although exposure of wild-type cells to TNF led to activation of nuclear factor-kappa B (NF-kappa B) and I kappa B alpha kinase, I kappa B alpha degradation, p65 phosphorylation, and p65 nuclear translocation, this cytokine had no effect on NQO2(-/-) cells. Deletion of NQO2 also abolished TNF-induced c-jun NH2-terminal kinase, Akt, p38, and p44/p42 mitogen-activated protein kinase activation. The induction of various antiapoptotic gene products (NIMP-9, cyclin D1, COX-2, IAP1, LAP2, Bcl-2, cFLIP, and XIAP) by TNF was also abolished in NQO2(-/-) cells. This correlated with potentiation of TNF-induced apoptosis as indicated by cell viability, Annexin V staining, and caspase activation. In agreement with this, we also found that TNF activated NQO2, and NQO2-specific small interfering RNA abrogated the TNF-induced NQO2 activity and NF-kappa B activation. Overall, our results indicate that deletion of NQO2 plays a differential role in TNF signaling pathway: by suppressing cell survival signals and potentiating TNF-induced apoptosis.