B-cell Translocation Gene 2 (BTG2) Stimulates Cellular Antioxidant Defenses through the Antioxidant Transcription Factor NFE2L2 in Human Mammary Epithelial Cells
B-cell Translocation Gene 2 (BTG2) Stimulates Cellular Antioxidant Defenses through the Antioxidant Transcription Factor NFE2L2 in Human Mammary Epithelial Cells
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DOI：
10.1074/jbc.m112.367433
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发表时间：
2012-09-07
影响因子：
4.8
通讯作者：
Rosen, Eliot M.
中科院分区：
文献类型：
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作者：
Karve, Tejaswita M.;Rosen, Eliot M.
b细胞易位基因2，BTG2，是BTG/TOB （b细胞易位基因/ ErbB2换能器）基因家族的一员，参与细胞周期调节、正常发育，并可能抑制肿瘤。此前，研究表明BTG2在人类乳腺癌中表达缺失或下调。我们现在报道BTG2保护人类乳腺上皮细胞免受过氧化氢和其他氧化剂引起的氧化应激。BTG2对氧化应激的保护作用与brca1无关，但需要抗氧化转录因子NFE2L2，并与过氧化氢酶和超氧化物歧化酶1和2等抗氧化酶的表达上调有关。BTG2对抗氧化基因表达的刺激也依赖于nfe2l2。我们进一步证明BTG2是NFE2L2的结合伙伴，并增加其转录活性。此外，BTG2可在几种nfe2l2应答基因的抗氧化反应元件（ARE）中检测到。最后，我们发现BTG2与NFE2L2结合，保护细胞免受氧化应激，并刺激抗氧化基因表达的能力需要box B，这是BTG2/TOB家族蛋白特征的一个短的高度保守的氨基酸基元，而不需要box a或c。这些发现表明BTG2作为NFE2L2的共激活剂在上调细胞抗氧化防御中起着新的作用。
The B-cell translocation gene 2, BTG2, a member of the BTG/TOB (B-cell translocation gene/transducers of ErbB2) gene family, has been implicated in cell cycle regulation, normal development, and possibly tumor suppression. Previously, it was shown that BTG2 expression is lost or down-regulated in human breast cancers. We now report that BTG2 protects human mammary epithelial cells from oxidative stress due to hydrogen peroxide and other oxidants. BTG2 protection against oxidative stress is BRCA1-independent but requires the antioxidant transcription factor NFE2L2 and is associated with up-regulation of the expression of antioxidant enzymes, including catalase and superoxide dismutases 1 and 2. BTG2 stimulation of antioxidant gene expression is also NFE2L2-dependent. We further demonstrate that BTG2 is a binding partner for NFE2L2 and increases its transcriptional activity. In addition, BTG2 is detectable at the antioxidant response element (ARE) of several NFE2L2-responsive genes. Finally, we show that the ability of BTG2 to associate with NFE2L2, to protect cells against oxidative stress, and to stimulate antioxidant gene expression requires box B, a short highly conserved amino acid motif characteristic of BTG2/TOB family proteins, but does not require boxes A or C. These findings suggest a novel role for BTG2 as a co-activator for NFE2L2 in up-regulating cellular antioxidant defenses.