SUPEROXIDE-INDUCIBLE PROTEIN A170 AND REDOX REGULATION

我们一直在表征编码小鼠巨噬细胞中新型氧化应激诱导蛋白的cDNA克隆。我们发现了一种名为A170的新型蛋白质，它具有锌指基序、PEST序列和几个潜在的蛋白激酶磷酸化位点。结构特征表明，它可能作为一种代谢调节剂，而不是作为一种抗氧化剂本身。低剂量的氧化应激剂如百草枯和马来酸二乙酯可以诱导巨噬细胞中的A170蛋白。在小鼠巨噬细胞中，我们已经发现了在体外磷酸化A170蛋白的蛋白激酶。使用特异性蛋白酶抑制剂，我们已经表明A170蛋白被蛋白酶体快速降解。我们还发现，微摩尔浓度的过氧化氢诱导A170蛋白的水平，而A170 mRNA的水平没有显着增加，这一结果表明，氧化应激可能会延缓A170蛋白在细胞中的降解。有趣的是，美国研究小组最近的报告显示，与A170 90%相同的人类蛋白质已被克隆为酪氨酸激酶LCK的SH2结构域的配体或EB病毒感染后诱导的新型细胞因子受体。这些结果表明，A170蛋白在氧化应激下的细胞内信号转导中起作用。

We have been characterizing cDNA clones that encode novel oxidative stress-inducible proteins from mouse macrophages. We have found a novel protein termed A170 that has a Zn-finger motif, a PEST-sequence and several potential phosphorylation sites for protein kinases. The structural features suggest that it may work as a metabolic regulator rather than as an antioxidant itself. The A170 protein can be induced in the macrophages by low doses of oxidative stress agents such as paraquat and diethyl maleate. In the murine macrophages, we have found protein kinases that phosphorylate A170 protein in vitro. Using specific protease inhibitors, we have suggested that A170 protein is rapidly degraded by proteasome. We also have shown that micromolar concentrations of hydrogen peroxide induced the level of A170 protein without significant increase in the level of A170 mRNA.This result suggests a possibility that oxidative stress may retard the degradation of A170 protein in the cells. Interestingly, recent reports by US research groups show that a human protein, 90% identical to A170, has been cloned either as an ligand to SH2 domain of tyrosine kinase LCK or to a novel cytokine receptor induced upon infection by EB-virus. These results suggest that the A170 protein plays a role in the intracellular signal transduction under oxidative stress.