Crossregulation of NF-κB by the APC/GSK-3β/β-catenin pathway
Crossregulation of NF-κB by the APC/GSK-3β/β-catenin pathway
复制标题
DOI：
10.1002/mc.10169
复制
发表时间：
2004-03-01
影响因子：
4.6
通讯作者：
Hung, MC
中科院分区：
文献类型：
--
作者：
Deng, J;Xia, WY;Hung, MC
糖原合成酶-3β(GSK-3β)和结肠腺瘤性息肉病(APC)在β-连环蛋白的调节中起着重要作用。其功能的抑制或缺陷可导致β-连环蛋白的激活。最近发现β-连环蛋白能与核因子kappaB相互作用并抑制核因子kappaB。然而，GSK3β/APC对核因子-kappaB信号通路的调节作用尚不清楚，因为它们的作用各不相同。在本研究中，我们研究了GSK-3β/APC是否可能通过β-连环蛋白调节核因子-kappaB的活性。我们发现，在APC突变细胞中，抑制GSK-3β抑制了NF-kappaB的活性，而重新表达APC则恢复了NF-kappaB的活性。这种调节作用是通过β-连环素实现的，因为在同一系统中，小干扰RNA(SiRNA)与β-连环素的缺失逆转了这一效应。对原发乳腺肿瘤组织的体内分析进一步支持了这种调控关系，在这些组织中，NF-kappaB靶标TRAF1与激活的β-连环蛋白呈负相关。因此，APC/GSK-3β可能通过β-连环蛋白交叉调节NF-kappaB信号通路。(C)2004年Wiley-Liss公司
Glycogen synthase kinase-3beta (GSK-3beta) and adenomatous polyposis coli (APC) play an important role in the regulation of beta-catenin. Inhibition of or defects in their functions can lead to activation of beta-catenin. beta-catenin has been recently found to interact with and inhibit nuclear factor kappa B (NF-kappaB). However, the regulatory roles of GSK3beta/APC on the NF-kappaB signaling pathway are unknown because of their diverse effects. in this study, we investigated whether GSK-3beta/APC might regulate NF-kappaB activity through beta-catenin. We found that inhibition of GSK-3beta suppressed NF-kappaB activity, whereas reexpression of APC restored NF-kappaB activity in APC mutated cells. The regulatory effects were through beta-catenin because depletion of beta-catenin with small interfering RNA (siRNA) in the same systems reversed the effects. The regulatory relationship was further supported by the analysis of primary breast tumor tissues in vivo in which NF-kappaB target TRAF1 was inversely correlated with activated beta-catenin. Thus, APC/GSK-3beta, through beta-catenin, may crossregulate NF-kappaB signaling pathway. (C) 2004 Wiley-Liss, Inc.