Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 46, Issue 1, Pages 95-104Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2008.09.039
Keywords
Antioxidant-1; SOD3; Copper; Transcription factor; Copper chaperone; Free radicals
Funding
- NIH [R01 HL70187, P01 HL58000, R01 HL 077524]
- AHA [0455242B, 0555308B, 0755805Z]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL070187, R01HL077524, P01HL058000] Funding Source: NIH RePORTER
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Extracellular superoxide dismutase (SOD3), a secretory copper-containing antioxidant enzyme, plays an important role in various oxidative stress-dependent cardiovascular diseases. Although cofactor copper is required for SOD3 activity, it remains unknown whether it can regulate SOD3 transcription. We previously demonstrated that SOD3 activity requires the copper chaperone antioxidant-1 (Atox1), involved in copper delivery to SOD3 at the trans-Golgi network (TGN). Here we show that copper treatment in mouse fibroblasts significantly increases mRNA and protein levels of SOD3, but not SOD1, which is abolished in Atox1-deficient cells. Copper promotes Atox1 translocation to the nucleus. Promoter deletion analysis identifies copper- and Atox1-response elements (REs) at the SOD3 promoter. Gel-shift and ChIP assays reveal that Atox1 directly binds to the Atox1 RE in a copper-dependent manner in vitro and in vivo. Adenovirus-mediated reexpression in Atox1(-/-) cells of nucleus-targeted Atox1 (Atox1-NLS), but not TGN-targeted Atox1 (Atox1-TGN), increases SOD3 transcription without affecting SOD3 activity. Importantly, reexpression of both Atox1-NLS and Atox1-TGN together, but not either alone, in Atox1(-/-) cells increases SOD3 activity. SOD3 transcription is positively regulated by copper through the transcription factor function of Atox1, whereas the full activity of SOD3 requires both the copper chaperone and the transcription factor functions of Atox1. Thus, Atox1 is a potential therapeutic target for oxidant stress-dependent cardiovascular disease. (C) 2008 Elsevier Inc. All rights reserved.
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