Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated mice
Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated mice
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DOI：
10.1093/carcin/bgp100
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发表时间：
2009-06-01
期刊：
影响因子：
4.7
通讯作者：
Kensler, Thomas W.
中科院分区：
文献类型：
--
作者：
Yates, Melinda S.;Tran, Quynh T.;Kensler, Thomas W.
由于无法产生适应性反应，NF-E2 相关因子 2 (Nrf2) 信号传导的缺失会增加小鼠对急性毒性、炎症和致癌的易感性。相比之下，尽管最近在一些人类癌症中发现了 Keap1 的失活突变，但破坏 Keap1（Nrf2 更新的细胞质修饰剂）可以防止小鼠免受这些应激。 Nrf2 激活的整体特征对于利用该通路对健康但处于危险中的个体进行化学预防以及阐明劫持该通路在 Keap1 突变人类癌症中的后果非常重要。肝脏靶向条件性 Keap1-null、Albumin-Cre:Keap1((flox/-)) (CKO) 小鼠提供了 Nrf2 信号传导基因激活的模型。通过将 CKO 小鼠的全局基因表达分析与使用合成齐墩果烷三萜类化合物 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]咪唑 (CDDO-Im) 的药理激活分析相结合，我们能够深入了解受 Nrf2 激活影响的途径。 CDDO-Im 是 Nrf2 信号传导的极有效激活剂。 CKO 小鼠用于鉴定受 Nrf2 信号传导基因激活调节的基因。将 CKO 反应与用最大 Nrf2 激活剂量的 CDDO-Im 治疗的野生型小鼠的肝脏整体基因表达变化进行比较。结果表明，Nrf2 信号传导的遗传和药理学激活可调节除毒和细胞保护之外的途径，其中最大的基因簇与脂质代谢相关。 Nrf2 的基因激活导致大量的解毒和脂质代谢基因变化。此外，药理学激活分析表明，Nrf2 是 CDDO-Im 活性的主要介质，尽管其他细胞信号传导靶点在口服剂量 30 μmol/kg 后也会受到调节。
Loss of NF-E2-related factor 2 (Nrf2) signaling increases susceptibility to acute toxicity, inflammation and carcinogenesis in mice due to the inability to mount adaptive responses. In contrast, disruption of Keap1 (a cytoplasmic modifier of Nrf2 turnover) protects against these stresses in mice, although inactivating mutations in Keap1 have been identified recently in some human cancers. Global characterization of Nrf2 activation is important to exploit this pathway for chemoprevention in healthy, yet at-risk individuals and also to elucidate the consequences of hijacking the pathway in Keap1-mutant human cancers. Liver-targeted conditional Keap1-null, Albumin-Cre:Keap1((flox/-)) (CKO) mice provide a model of genetic activation of Nrf2 signaling. By coupling global gene expression analysis of CKO mice with analysis of pharmacologic activation using the synthetic oleanane triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), we are able to gain insight into pathways affected by Nrf2 activation. CDDO-Im is an extremely potent activator of Nrf2 signaling. CKO mice were used to identify genes modulated by genetic activation of Nrf2 signaling. The CKO response was compared with hepatic global gene expression changes in wild-type mice treated with CDDO-Im at a maximal Nrf2 activating dose. The results show that genetic and pharmacologic activation of Nrf2 signaling modulates pathways beyond detoxication and cytoprotection, with the largest cluster of genes associated with lipid metabolism. Genetic activation of Nrf2 results in much larger numbers of detoxication and lipid metabolism gene changes. Additionally, analysis of pharmacologic activation suggests that Nrf2 is the primary mediator of CDDO-Im activity, though other cell-signaling targets are also modulated following an oral dose of 30 mu mol/kg.