Transcriptional repression of catalase in mouse skin tumor progression
Transcriptional repression of catalase in mouse skin tumor progression
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DOI：
10.1593/neo.04127
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发表时间：
2004-09-01
期刊：
影响因子：
4.8
通讯作者：
Bowden, GT
中科院分区：
文献类型：
--
作者：
Kwei, KA;Finch, JS;Bowden, GT
我们实验室以前的研究表明，活性氧水平的升高和抗氧化酶过氧化氢酶的抑制在良性乳头状瘤细胞向恶性癌细胞的体外进展中发挥了关键作用。发现过氧化氢酶信息、蛋白水平和活性水平在恶性进展的细胞中下调。本研究的目的是进一步表征过氧化氢酶在小鼠皮肤肿瘤恶性进展中的抑制作用。为了验证体外观察结果，我们研究了多步化学致癌方案产生的肿瘤样品中的过氧化氢酶表达。在良性乳头状瘤中观察到过氧化氢酶mRNA和蛋白水平高于恶性肿瘤。核连续分析表明，过氧化氢酶抑制在培养的恶性细胞是转录依赖性的。从荧光素酶报告基因分析的结果表明，恶性细胞有较低的过氧化氢酶启动子活性比良性乳头状瘤细胞，部分通过Wilm的肿瘤抑制因子1（WT 1）结合位点内的近端启动子区域。发现WT1蛋白水平与观察到的过氧化氢酶启动子活性呈负相关，在恶性细胞中观察到的水平高于良性细胞。这些结果使我们得出结论，WT1是作为一个转录抑制剂在过氧化氢酶基因调控在肿瘤的进展。
Previous studies in our laboratory have shown that the elevation of reactive oxygen species levels and the repression of the antioxidant enzyme, catalase, played a critical role in the in vitro progression of benign papilloma cells to malignant carcinoma cells. Catalase message, protein levels, and activity levels were found to be downregulated in the malignantly progressed cells. The goal of this study is to further characterize the repression of catalase in malignant progression of mouse skin tumors. To validate the in vitro observations, we examined catalase expression in tumor samples generated by the multistep chemical carcinogenesis protocol. Higher levels of catalase mRNA and protein were observed in benign papillomas versus malignant carcinomas. Nuclear run-on analysis showed that catalase repression in the cultured malignant cells was transcription-dependent. Results from luciferase reporter assays indicated that malignant cells have lower catalase promoter activities than benign papilloma cells, in part through the Wilm's tumor suppressor 1 (WT1) binding site within the proximal promoter region. The WT1 protein levels were found to be inversely correlated with the observed catalase promoter activities, with higher levels observed in the malignant cells versus the benign cells. These results led us to conclude that WT1 is acting as a transcription repressor in catalase gene regulation during tumor progression.