An Nrf2 small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements
An Nrf2 small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements
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DOI：
10.1006/bbrc.1997.6943
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发表时间：
1997-07-18
影响因子：
3.1
通讯作者：
Nabeshima, Y
中科院分区：
文献类型：
--
作者：
Itoh, K;Chiba, T;Nabeshima, Y
第二阶段解毒酶的诱导是一个重要的防御机制，对摄入外源性物质。虽然这组酶被认为是在抗氧化反应元件（战神）的转录控制下，但这一论点尚未得到实验证实。由于ARE类似于红系转录因子NF-E2的结合序列，我们研究了II相酶基因可能受也与NF-E2序列类似的转录因子调控的可能性。许多转录因子的表达谱表明，Nrf 2/小Maf异源二聚体是最有可能在体内发挥这一作用的候选者。为了直接测试这些问题，我们在体内破坏了小鼠nrf 2基因。而II期酶（例如，谷胱甘肽S-转移酶和NAD（P）H：醌氧化还原酶）在野生型和杂合突变小鼠体内均被酚类抗氧化剂显著诱导，但在纯合nrf 2突变小鼠的肝脏和肠中，这种诱导作用基本上被消除。发现Nrf 2仅作为具有小Maf蛋白的异二聚体以高亲和力结合ARE，表明Nrf 2/小Maf直接通过ARE激活基因表达。这些结果表明，Nrf 2是必不可少的II相酶的转录诱导和II相酶基因的协调转录调控机制的存在。nrf 2基因缺陷的小鼠可能被证明是一个非常有用的模型，在体内分析化学致癌和抗癌药物的耐药性。(C)北京：科学出版社.
The induction of phase II detoxifying enzymes is an important defense mechanism against intake of xenobiotics. While this group of enzymes is believed to be under the transcriptional control of antioxidant response elements (AREs), this contention is experimentally unconfirmed. Since the ARE resembles the binding sequence of erythroid transcription factor NF-E2, we investigated the possibility that the phase II enzyme genes might be regulated by transcription factors that also kind to the NF-E2 sequence. The expression profiles of a number of transcription factors suggest that an Nrf2/small Maf heterodimer is the most likely candidate to fulfill this role in vivo. To directly test these questions, we disrupted the murine nrf2 gene in vivo. While the expression of phase II enzymes (e.g., glutathione S-transferase and NAD(P)H: quinone oxidoreductase) was markedly induced by a phenolic antioxidant in vivo in both wild type and heterozygous mutant mice, the induction was largely eliminated in the liver and intestine of homozygous nrf2-mutant mice. Nrf2 was found to bind to the ARE with high affinity only as a heterodimer with a small Maf protein, suggesting that Nrf2/small Maf activates gene expression directly through the ARE. These results demonstrate that Nrf2 is essential for the transcriptional induction of phase II enzymes and the presence of a coordinate transcriptional regulatory mechanism for phase II enzyme genes. The nrf2-deficient mice may prove to be a very useful model for the in vivo analysis of chemical carcinogenesis and resistance to anti-cancer drugs. (C) 1997 Academic Press.