Department of Genetics, Louisiana State University Health Sciences Center, 533 Bolivar Street, CSRB 6th floor, New Orleans, LA 70112, USA.
Biochem Biophys Res Commun. 2011 Jan 28;404(4):963-7. doi: 10.1016/j.bbrc.2010.12.089. Epub 2010 Dec 24.
FOXO1, a member of the winged-helix family of transcription factors, is a ubiquitously expressed protein involved in regulating a variety of cellular processes including glucose homeostasis, apoptosis, cell cycle control, muscle differentiation, and angiogenesis. In addition to these biological functions, FOXO1 is a key player in the oxidative stress response by stimulating the expression of metal-containing anti-oxidant proteins such as manganese superoxide dismutase, selenoprotein P, and catalase. Evidence in the literature suggests that FOXO1 may also be capable of regulating the expression of the anti-oxidant protein Ceruloplasmin (Cp), a six-copper-containing protein synthesized and secreted mainly by the liver. In the present report, we demonstrate that FOXO1 stimulates Cp promoter activity in conjunction with the cytokine IL-6. Through deletional analysis and in vitro binding studies, we determine the DNA sequence responsible for the FOXO1-dependent regulation of the Cp proximal promoter. Finally, we demonstrate that FOXO1 is capable of enhancing the expression of endogenous Cp in human hepatic carcinoma cells treated with IL-6. These results allow us to identify FOXO1 as a regulator of Cp expression to promote the anti-oxidant pathway in response to IL-6 signaling.
叉头框蛋白 O1（FOXO1）是螺旋-环-螺旋转录因子家族的成员，是一种广泛表达的蛋白，参与调节多种细胞过程，包括葡萄糖稳态、细胞凋亡、细胞周期控制、肌肉分化和血管生成。除了这些生物学功能外，FOXO1 还是氧化应激反应的关键参与者，通过刺激含金属的抗氧化蛋白（如锰超氧化物歧化酶、硒蛋白 P 和过氧化氢酶）的表达来发挥作用。文献中的证据表明，FOXO1 可能还能够调节抗氧化蛋白铜蓝蛋白（Cp）的表达，Cp 是一种主要由肝脏合成和分泌的含六铜蛋白。在本报告中，我们证明 FOXO1 与细胞因子 IL-6 一起刺激 Cp 启动子活性。通过缺失分析和体外结合研究，我们确定了负责 FOXO1 依赖性调节 Cp 近端启动子的 DNA 序列。最后，我们证明 FOXO1 能够增强人肝癌细胞中内源性 Cp 在接受 IL-6 处理时的表达。这些结果使我们能够将 FOXO1 鉴定为 Cp 表达的调节剂，以促进抗氧化途径对 IL-6 信号的反应。
