Functional characterization and role of INrf2 in antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase 1 gene
Functional characterization and role of INrf2 in antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase 1 gene
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DOI：
10.1038/sj.onc.1204506
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发表时间：
2001-06-28
期刊：
影响因子：
8
通讯作者：
Jaiswal, AK
中科院分区：
文献类型：
--
作者：
Dhakshinamoorthy, S;Jaiswal, AK
已知抗氧化剂应答元件（ARE）和核转录因子Nrf 2响应于抗氧化剂和异生物质调节NQO 1和其它解毒酶基因的表达和协调诱导。Nrf 2的胞质抑制剂INrf 2将Nrf 2保留在细胞质中，其被克隆和测序。用抗氧化剂和异生物质处理细胞导致Nrf 2从INrf 2释放，然后Nrf 2在细胞核中移动，这导致ARE介导的NQO 1和其他解毒酶基因的表达被诱导，INrf 2与Nrf 2解离后留在胞质溶胶中，INrf 2的过表达抑制ARE介导的NQO 1基因的表达，INrf 2的缺失定位揭示了KELCH结构域的需要（氨基酸残基361-597）和C-末端区域（氨基酸残基598-624）在胞质溶胶中保留Nrf 2，INrf 2的这两个区域独立地将Nrf 2保留在胞质溶胶中，导致ARE介导的NQO 1基因表达的抑制，这些结果可能表明，两个不同的区域的Nrf 2与一个分子的Nrf 2或两个或更多个分子的Nrf 2与一个分子的INrf 2的相互作用，Nrf 2和INrf 2的转录没有改变，以响应抗氧化剂和外源性物质，这表明，INrf 2和/或Nrf 2可能是转录后修饰，以响应抗氧化剂和外源性物质，导致Nrf 2从INrf 2释放和诱导ARE介导的NQO 1和其他解毒酶基因的表达。
Antioxidant response element (ARE) and nuclear transcription factor Nrf2 are known to regulate expression and coordinated induction of NQO1 and other detoxifying enzyme genes in response to antioxidants and xenobiotics, A cytosolic inhibitor of Nrf2, INrf2, that retains Nrf2 in the cytoplasm, was cloned and sequenced, Treatment of cells with antioxidants and xenobiotics results in the release of Nrf2 from INrf2, Nrf2 then moves in the nucleus, This leads to the induction of ARE-mediated NQO1 and other detoxifying enzyme genes expression, INrf2 after dissociation from Nrf2 remains in the cytosol, Overexpression of INrf2 repressed ARE-mediated NQO1 gene expression, Deletion mapping of INrf2 revealed the requirement of KELCH domain (amino acid residues 361-597) and C-terminal region (amino acid residues 598-624) in retention of Nrf2 in the cytosol, Both these regions of INrf2 independently retained Nrf2 in the cytosol leading to the repression of ARE-mediated NQO1 gene expression, These results may indicate that two different regions of INrf2 interact with a single molecule of Nrf2 or two or more molecules of Nrf2 interact with a single molecule of INrf2, The transcription of Nrf2 and INrf2 did not change in response to antioxidants and xenobiotics, This indicated that INrf2 and/or Nrf2 might be post-transcriptionally modified in response to antioxidants and xenobiotics leading to the release of Nrf2 from INrf2 and induction of ARE-mediated NQO1 and other detoxifying enzyme genes expression.