Transcription of mammalian cytochrome c oxidase subunit IV-2 is controlled by a novel conserved oxygen responsive element.
Subunit 4 of cytochrome c oxidase (CcO) is a nuclear-encoded regulatory subunit of the terminal complex of the mitochondrial electron transport chain. We have recently discovered an isoform of CcO 4 (CcO4-2) which is specific to lung and trachea, and is induced after birth. The role of CcO as the major cellular oxygen consumer, and the lung-specific expression of CcO4-2, led us to investigate CcO4-2 gene regulation. We cloned the CcO4-2 promoter regions of cow, rat and mouse and compared them with the human promoter. Promoter activity is localized within a 118-bp proximal region of the human promoter and is stimulated by hypoxia, reaching a maximum (threefold) under 4% oxygen compared with normoxia. CcO4-2 oxygen responsiveness was assigned by mutagenesis to a novel promoter element (5'-GGACGTTCCCACG-3') that lies within a 24-bp region that is 79% conserved in all four species. This element is able to bind protein, and competition experiments revealed that, within the element, the four core bases 5'-TCNCA-3' are obligatory for transcription factor binding. CcO isolated from lung showed a 2.5-fold increased maximal turnover compared with liver CcO. We propose that CcO4-2 expression in highly oxygenated lung and trachea protects these tissues from oxidative damage by accelerating the last step in the electron transport chain, leading to a decrease in available electrons for free radical formation.
Hüttemann
Maik
M
Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA. mhuttema@med.wayne.edu
Lee
Icksoo
I
Liu
Jenney
J
Grossman
Lawrence I
LI
D000818:Animals; D001483:Base Sequence; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D003576:Electron Transport Complex IV / Q000235:genetics* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008168:Lung / Q000378:metabolism; D008322:Mammals; D051379:Mice; D008969:Molecular Sequence Data; D010100:Oxygen / Q000378:metabolism*; D010802:Phylogeny; D011401:Promoter Regions, Genetic; D051381:Rats; D020218:Response Elements; D014158:Transcription, Genetic; D014162:Transfection
D003576:Electron Transport Complex IV; D010100:Oxygen