Transforming growth factor-β induces transcription factors MafK and Bach1 to suppress expression of the heme oxygenase-1 gene.
Transforming growth factor-β induces transcription factors MafK and Bach1 to suppress expression of the heme oxygenase-1 gene.
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DOI：
10.1074/jbc.m113.450478
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发表时间：
2013-07-12
期刊：
影响因子：
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通讯作者：
Kato M
中科院分区：
文献类型：
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作者：
Okita Y;Kamoshida A;Suzuki H;Itoh K;Motohashi H;Igarashi K;Yamamoto M;Ogami T;Koinuma D;Kato M
背景：TGF-β 抑制早期癌发生，但通过激活侵袭和转移加速恶性进展。 HO-1 是响应氧化应激而诱导的，可保护细胞免受氧化损伤。结果：TGF-β 通过诱导 MafK 和 Bach1 抑制 tBHQ 诱导的 HO-1 表达。结论：TGF-β 抑制对亲电子试剂的保护性反应。意义：这项工作提供了 TGF-β 影响亲电子反应的第一个证据。转化生长因子-β (TGF-β) 在胚胎发生、成人稳态、组织修复和癌症发展中具有多种功能。在此，我们报道 TGF-β 抑制血红素加氧酶-1 (HO-1) 基因的转录激活，该基因与防止氧化损伤和肺癌发生有关。 HO-1 是氧化应激反应转录因子 Nrf2 的靶标。在用亲电试剂刺激后，TGF-β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。即使在细胞核中存在累积的 Nrf2 的情况下，MafK 或 Bach1 的表达增强也足以抑制 HO-1 的亲电子诱导表达。通过 siRNA 敲除 MafK 和 Bach1，消除了 TGF-β 依赖性的 HO-1 抑制。此外，染色质免疫沉淀分析显示，Nrf2 在抗氧化反应元件（E1 和 E2）上替代了 Bach1，后者负责诱导 HO-1 响应氧化应激。另一方面，用TGF-β预处理抑制了Nrf2与E1和E2的结合，但略微增加了MafK与Smads一起与E2的结合。由于 TGF-β 在组织损伤后和癌症发展过程中被激活，这些发现表明了一种新的机制，通过这种机制，受损组织变得容易受到氧化应激和异生素的影响。
Background: TGF-β suppresses early carcinogenesis but accelerates malignant progression by activating invasion and metastasis. HO-1 is induced in response to oxidative stress and protects cells from oxidative injury. Results: TGF-β suppresses tBHQ-inducible expression of HO-1 through induction of MafK and Bach1. Conclusion: TGF-β suppresses a protective response to electrophiles. Significance: This work provides the first evidence that TGF-β affects electrophilic responses. 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.