title: Oxygen-dependent expression of cytochrome c oxidase subunit 4-2 gene expression is mediated by transcription factors RBPJ, CXXC5 and CHCHD2.
abstract: Cytochrome c oxidase (COX) is the terminal enzyme of the electron transport chain, made up of 13 subunits encoded by both mitochondrial and nuclear DNA. Subunit 4 (COX4), a key regulatory subunit, exists as two isoforms, the ubiquitous isoform 1 and the tissue-specific (predominantly lung) isoform 2 (COX4I2). COX4I2 renders lung COX about 2-fold more active compared with liver COX, which lacks COX4I2. We previously identified a highly conserved 13-bp sequence in the proximal promoter of COX4I2 that functions as an oxygen responsive element (ORE), maximally active at a 4% oxygen concentration. Here, we have identified three transcription factors that bind this conserved ORE, namely recombination signal sequence-binding protein Jκ (RBPJ), coiled-coil-helix-coiled-coil-helix domain 2 (CHCHD2) and CXXC finger protein 5 (CXXC5). We demonstrate that RBPJ and CHCHD2 function towards activating the ORE at 4% oxygen, whereas CXXC5 functions as an inhibitor. To validate results derived from cultured cells, we show using RNA interference a similar effect of these transcription factors in the gene regulation of COX4I2 in primary pulmonary arterial smooth muscle cells. Depending on the oxygen tension, a concerted action of the three transcription factors regulates the expression of COX4I2 that, as we discuss, could augment both COX activity and its ability to cope with altered cellular energy requirements.
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, School of Medicine, Detroit, MI 48201, USA.
authors.forename: Siddhesh
authors.initials: S
authors.lastname: Aras
authors.forename: Oleg
authors.initials: O
authors.lastname: Pak
authors.forename: Natascha
authors.initials: N
authors.lastname: Sommer
authors.forename: Russell
authors.initials: R
authors.lastname: Finley
authors.forename: Maik
authors.initials: M
authors.lastname: Hüttemann
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Lawrence I
authors.initials: LI
authors.lastname: Grossman
mesh_terms: D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D003576:Electron Transport Complex IV / Q000096:biosynthesis / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D024101:Mitochondrial Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D010100:Oxygen / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism; D020218:Response Elements; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: C580880:CHCHD2 protein, human; C540448:CXXC5 protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D024101:Mitochondrial Proteins; C497570:RBPJ protein, human; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C539675:COX4I2 protein, human; D003576:Electron Transport Complex IV; D010100:Oxygen