Oxygen-dependent expression of cytochrome c oxidase subunit 4-2 gene expression is mediated by transcription factors RBPJ, CXXC5 and CHCHD2
Open Access
- 8 January 2013
- journal article
- research article
- Published by Oxford University Press (OUP) in Nucleic Acids Research
- Vol. 41 (4), 2255-2266
- https://doi.org/10.1093/nar/gks1454
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.Keywords
This publication has 40 references indexed in Scilit:
- A Computational Screen for Regulators of Oxidative Phosphorylation Implicates SLIRP in Mitochondrial RNA HomeostasisPLoS Genetics, 2009
- Zinc Coordination Is Required for and Regulates Transcription Activation by Epstein-Barr Nuclear Antigen 1PLoS Pathogens, 2009
- Functional involvement of RINF, retinoid-inducible nuclear factor (CXXC5), in normal and tumoral human myelopoiesisBlood, 2009
- CXXC5 Is a Novel BMP4-regulated Modulator of Wnt Signaling in Neural Stem CellsJournal of Biological Chemistry, 2009
- Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensorBlood, 2007
- CDD: a conserved domain database for interactive domain family analysisNucleic Acids Research, 2007
- Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchangeProceedings of the National Academy of Sciences of the United States of America, 2006
- Kaposi's Sarcoma-Associated Herpesvirus Lytic Switch Protein Stimulates DNA Binding of RBP-Jk/CSL To Activate the Notch PathwayJournal of Virology, 2006
- Induction of activating transcription factor 3 by anoxia is independent of p53 and the hypoxic HIF signalling pathwayOncogene, 2006
- IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon inductionNature Immunology, 2005