Overexpression of transcription factor AP-2 stimulates the PA promoter of the human uracil-DNA glycosylase (UNG) gene through a mechanism involving derepression |
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| Authors: | Per Arne Aas Javier Peña-Diaz Nina Beate Liabakk Hans E. Krokan Frank Skorpen |
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| Affiliation: | 1. Department of Cancer Research and Molecular Medicine, Children''s and Women''s Health, Faculty of Medicine, Norwegian University of Science and Technology, N-7489 Trondheim, Norway;2. Department of Laboratory Medicine, Children''s and Women''s Health, Faculty of Medicine, Norwegian University of Science and Technology, N-7489 Trondheim, Norway;1. Department of Molecular Biology & Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, United States;2. Department of Diabetes, Endocrinology and Metabolic Diseases, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, United States;3. Bioinformatics Core, Department of Molecular Medicine, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, United States;3. Department of Biology, University of Padova, 35131 Padova, Italy;4. CRIBI Biotechnology Centre, University of Padova, 35131 Padova, Italy;5. MicroScoBio Research Center, Department of Experimental Medicine, University of Genova, 16132 Genova, Italy;12. Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy;6. Experimental Imaging Center, San Raffaele Scientific Institute, 20132 Milano, Italy |
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| Abstract: | The PA promoter in the human uracil-DNA glycosylase gene (UNG) directs expression of the nuclear form (UNG2) of UNG proteins. Using a combination of promoter deletion and mutation analyses, and transient transfection of HeLa cells, we show that repressor and derepressor activities are contained within the region of DNA marked by PA. Footprinting analysis and electrophoretic mobility shift assays of PA and putative AP-2 binding regions with HeLa cell nuclear extract and recombinant AP-2α protein indicate that AP-2 transcription factors are central in the regulated expression of UNG2 mRNA. Chromatin immunoprecipitation with AP-2 antibody demonstrated that endogenous AP-2 binds to the PA promoter in vivo. Overexpression of AP-2α, -β or -γ all stimulated expression from a PA-luciferase reporter gene construct approximately 3- to 4-fold. Interestingly, an N-terminally truncated AP-2α, lacking the activation domain but retaining the DNA binding and dimerization domains, stimulated PA to a level approaching that of full-length AP-2, suggesting that AP-2 overexpression stimulates PA activity by a mechanism involving derepression rather than activation, possibly by neutralizing an inhibitory effect of endogenous AP-2 or AP-2-like factors. |
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