Coactivator MBF1 preserves the redox-dependent AP-1 activity during oxidative stress in Drosophila
Coactivator MBF1 preserves the redox-dependent AP-1 activity during oxidative stress in Drosophila
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DOI：
10.1038/sj.emboj.7600356
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发表时间：
2004-09-01
期刊：
影响因子：
11.4
通讯作者：
Hirose, S
中科院分区：
文献类型：
--
作者：
Jindra, M;Gaziova, I;Hirose, S
碱性亮氨酸拉链蛋白 Jun 和 Fos 形成二聚体转录因子 AP-1，对于细胞分化以及免疫和抗氧化防御至关重要。 AP-1 活性部分由 Jun 和 Fos 基本区域内关键半胱氨酸残基的氧化还原状态控制。这些半胱氨酸的突变有助于 Jun 和 Fos 的致癌潜力。细胞如何将氧化还原依赖性 AP-1 活性维持在有利的水平尚不清楚。我们证明保守的共激活剂 MBF1 是 AP-1 的正调节剂。通过与果蝇 Jun (D-Jun) 的基本区域直接相互作用，MBF1 可以防止关键半胱氨酸的氧化修饰（S-半胱烯基半胱氨酸化）并刺激 AP-1 与 DNA 结合。细胞质 MBF1 与转染的 D-Jun 蛋白一起易位到细胞核，表明 MBF1 也在果蝇细胞中保护新生的 D-Jun。在过氧化氢 (H2O2) 存在下，mbf1-null 突变体的寿命比 mbf1(+) 对照短。在缺乏 MBF1 的果蝇中，AP-1 依赖性上皮闭合对 H2O2 变得敏感。我们的结论是，通过保留氧化还原敏感的 AP-1 活性，MBF1 在氧化应激期间提供了优势。
Basic leucine zipper proteins Jun and Fos form the dimeric transcription factor AP-1, essential for cell differentiation and immune and antioxidant defenses. AP-1 activity is controlled, in part, by the redox state of critical cysteine residues within the basic regions of Jun and Fos. Mutation of these cysteines contributes to oncogenic potential of Jun and Fos. How cells maintain the redox-dependent AP-1 activity at favorable levels is not known. We show that the conserved coactivator MBF1 is a positive modulator of AP-1. Via a direct interaction with the basic region of Drosophila Jun (D-Jun), MBF1 prevents an oxidative modification (S-cystenyl cystenylation) of the critical cysteine and stimulates AP-1 binding to DNA. Cytoplasmic MBF1 translocates to the nucleus together with a transfected D-Jun protein, suggesting that MBF1 protects nascent D-Jun also in Drosophila cells. mbf1-null mutants live shorter than mbf1(+) controls in the presence of hydrogen peroxide (H2O2). An AP-1-dependent epithelial closure becomes sensitive to H2O2 in flies lacking MBF1. We conclude that by preserving the redox-sensitive AP-1 activity, MBF1 provides an advantage during oxidative stress.