Transcriptional repression of catalase in mouse skin tumor progression.
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.
Kwei
Kevin A
KA
Department of Radiation Oncology, Arizona Cancer Center, University of Arizona, 1515 North Campbell Avenue, Tucson, AZ 85724, USA.
Finch
Joanne S
JS
Thompson
Eric J
EJ
Bowden
G Tim
GT
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D002374:Catalase / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D003609:Dactinomycin / Q000494:pharmacology; D015536:Down-Regulation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter / Q000235:genetics; D007633:Keratins / Q000032:analysis; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D051379:Mice; D009154:Mutation / Q000235:genetics; D010212:Papilloma / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D025721:WT1 Proteins / Q000378:metabolism
D012333:RNA, Messenger; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D025721:WT1 Proteins; D003609:Dactinomycin; D007633:Keratins; D002374:Catalase; D008156:Luciferases