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转化生长因子-β诱导转录因子 MafK 和 Bach1 抑制血红素加氧酶-1 基因的表达。

Transforming growth factor-β induces transcription factors MafK and Bach1 to suppress expression of the heme oxygenase-1 gene.

机构信息

Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan.

出版信息

J Biol Chem. 2013 Jul 12;288(28):20658-67. doi: 10.1074/jbc.M113.450478. Epub 2013 Jun 4.

DOI:10.1074/jbc.M113.450478
PMID:23737527
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3711329/
Abstract

Transforming growth factor-β (TGF-β) has multiple functions in embryogenesis, adult homeostasis, tissue repair, and development of cancer. Here, we report that TGF-β suppresses the transcriptional activation of the heme oxygenase-1 (HO-1) gene, which is implicated in protection against oxidative injury and lung carcinogenesis. HO-1 is a target of the oxidative stress-responsive transcription factor Nrf2. TGF-β did not affect the stabilization or nuclear accumulation of Nrf2 after stimulation with electrophiles. Instead, TGF-β induced expression of transcription factors MafK and Bach1. Enhanced expression of either MafK or Bach1 was enough to suppress the electrophile-inducible expression of HO-1 even in the presence of accumulated Nrf2 in the nucleus. Knockdown of MafK and Bach1 by siRNA abolished TGF-β-dependent suppression of HO-1. Furthermore, chromatin immunoprecipitation assays revealed that Nrf2 substitutes for Bach1 at the antioxidant response elements (E1 and E2), which are responsible for the induction of HO-1 in response to oxidative stress. On the other hand, pretreatment with TGF-β suppressed binding of Nrf2 to both E1 and E2 but marginally increased the binding of MafK to E2 together with Smads. As TGF-β is activated after tissue injury and in the process of cancer development, these findings suggest a novel mechanism by which damaged tissue becomes vulnerable to oxidative stress and xenobiotics.

摘要

转化生长因子-β（TGF-β）在胚胎发生、成人内稳态、组织修复和癌症发展中具有多种功能。在这里，我们报告 TGF-β 抑制血红素加氧酶-1（HO-1）基因的转录激活，该基因参与保护免受氧化损伤和肺癌发生。HO-1 是氧化应激反应转录因子 Nrf2 的靶标。TGF-β 在用亲电子试剂刺激后不影响 Nrf2 的稳定或核积累。相反，TGF-β 诱导转录因子 MafK 和 Bach1 的表达。表达增强的 MafK 或 Bach1 足以抑制亲电子诱导的 HO-1 表达，即使核中积累了 Nrf2。通过 siRNA 敲低 MafK 和 Bach1 可消除 TGF-β 对 HO-1 的依赖性抑制。此外，染色质免疫沉淀分析表明，Nrf2 取代 Bach1 结合到抗氧化反应元件（E1 和 E2），这是对氧化应激诱导 HO-1 表达的负责。另一方面，TGF-β 的预处理抑制了 Nrf2 与 E1 和 E2 的结合，但适度增加了 MafK 与 E2 结合，同时与 Smads 结合。由于 TGF-β 在组织损伤后和癌症发展过程中被激活，这些发现表明受损组织易受氧化应激和外源性物质影响的新机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ec5/3711329/dfdda7b1bde6/zbc0331355860007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ec5/3711329/ef447844b53a/zbc0331355860001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ec5/3711329/d760fa8ad416/zbc0331355860005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ec5/3711329/48440b6378ae/zbc0331355860006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ec5/3711329/dfdda7b1bde6/zbc0331355860007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ec5/3711329/ef447844b53a/zbc0331355860001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ec5/3711329/434d0cb8cd95/zbc0331355860002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ec5/3711329/71fd0643bc09/zbc0331355860003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ec5/3711329/20c2245815fe/zbc0331355860004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ec5/3711329/d760fa8ad416/zbc0331355860005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ec5/3711329/48440b6378ae/zbc0331355860006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ec5/3711329/dfdda7b1bde6/zbc0331355860007.jpg

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