Role of Bach1 and Nrf2 in up-regulation of the heme oxygenase-1 gene by cobalt protoporphyrin
Role of Bach1 and Nrf2 in up-regulation of the heme oxygenase-1 gene by cobalt protoporphyrin
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DOI：
10.1096/fj.06-6346fje
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发表时间：
2006-12-01
期刊：
影响因子：
4.8
通讯作者：
Bonkovsky, Herbert L.
中科院分区：
文献类型：
--
作者：
Shan, Ying;Lambrecht, Richard W.;Bonkovsky, Herbert L.
血红素加氧酶(HO)通过释放铁和一氧化碳催化血红素转化为胆绿素。HO-1受到多种物理和化学因素的高度诱导。CoPP被认为是许多组织中HO-1活性的有力和有效的诱导剂。在此，我们报道CoPP通过Bach1和Nrf2上调人肝细胞中HO-1的表达。COPP对肝脏Bach1和Nrf2mRNA水平无影响，但通过增加Bach1蛋白的降解(t(1/2)从19h到2.8h)显著降低Bach1蛋白的水平，通过减少Nrf2蛋白的降解(t(1/2)从2.5h到9h)显著增加Nrf2的水平。用Bach1-siRNA沉默Bach1可显著提高HO-1的mRNA和蛋白水平，加入CoPP可进一步上调HO-1的mRNA和蛋白表达。然而，与单独使用CoPP相比，Nrf2-siRNA沉默Nrf2 mRNA并没有显著改变基线HO-1mRNA或蛋白水平，但显著降低了5-10muM CoPP介导的HO-1mRNA水平的上调。同样数量的非Bach1或Nrf2相关的对照siRNA没有降低Bach1或Nrf2的mRNA或蛋白，证实了Bach1-和Nrf2-siRNA在Huh-7细胞中的特异性。我们的结论是，CoPP介导的HO-1诱导途径涉及Bach1的抑制和转录后位点(S)对NRF2蛋白的上调。由于CoPP与血红素不同，既不是HO-1的促氧化剂，也不是HO-1的底物，因此在需要上调HO-1的情况下，它可能被认为是一种潜在的治疗剂。
Heme oxygenase (HO) catalyzes the conversion of heme to biliverdin with the release of iron and carbon monoxide. HO-1 is highly inducible by a large number of physical and chemical factors. CoPP is known to be a potent and effective inducer of HO-1 activity in many tissues. Here we report that CoPP up-regulates HO-1 via Bach1 and Nrf2 in human liver cells. CoPP did not influence hepatic Bach1 or Nrf2 mRNA levels, but markedly reduced Bach1 protein levels by increasing degradation of Bach1 protein (t(1/2) from 19 h to 2.8 h), and increased Nrf2 by decreasing degradation of Nrf2 protein (t(1/2) from 2.5 h to 9 h). Silencing Bach1 by Bach1-siRNA significantly increased levels of HO-1 mRNA and protein, and addition of CoPP up-regulated HO-1 mRNA and protein further. However, silencing Nrf2 mRNA by Nrf2-siRNA did not significantly change baseline HO-1 mRNA or protein levels, but significantly decreased 5-10 mu M CoPP-mediated up-regulation of HO-1 mRNA levels compared with CoPP alone. Transfection with equal amounts of non-Bach1 or non-Nrf2 related control siRNA did not reduce Bach1 or Nrf2 mRNA or protein, confirming the specificity of Bach1-and Nrf2-siRNA in Huh-7 cells. We conclude that the pathway of CoPP-mediated induction of HO-1 involves the repression of Bach1 and up-regulation of the Nrf2 protein by post-transcriptional site(s) of action. Because CoPP, unlike heme, is neither a prooxidant nor a substrate for HO-1, it might be considered as a potential therapeutic agent in situations where up-regulation of HO-1 is desired.