Transcriptional Regulation of Yeast Oxidative Phosphorylation Hypoxic Genes by Oxidative Stress
Publication: Antioxidants & Redox Signaling
Volume 19, Issue Number 16
Abstract
Aims: Mitochondrial cytochrome c oxidase (COX) subunit 5 and cytochrome c (Cyc) exist in two isoforms, transcriptionally regulated by oxygen in yeast. The gene pair COX5a/CYC1 encodes the normoxic isoforms (Cox5a and iso1-Cyc) and the gene pair COX5b/CYC7 encodes the hypoxic isoforms (Cox5b and iso2-Cyc). Rox1 is a transcriptional repressor of COX5b/CYC7 in normoxia. COX5b is additionally repressed by Ord1. Here, we investigated whether these pathways respond to environmental and mitochondria-generated oxidative stress. Results: The superoxide inducer menadione triggered a significant de-repression of COX5b and CYC7. Hydrogen peroxide elicited milder de-repression effects that were enhanced in the absence of Yap1, a key determinant in oxidative stress resistance. COX5b/CYC7 was also de-repressed in wild-type cells treated with antimycin A, a mitochondrial bc1 complex inhibitor that increases superoxide production. Exposure to menadione and H2O2 enhanced both, Hap1-independent expression of ROX1 and Rox1 steady-state levels without affecting Ord1. However, oxidative stress lowered the occupancy of Rox1 on COX5b and CYC7 promoters, thus inducing their de-repression. Innovation: Reactive oxygen species (ROS)-induced hypoxic gene expression in normoxia involves the oxygen-responding Rox1 transcriptional machinery. Contrary to what occurs in hypoxia, ROS enhances Rox1 accumulation. However, its transcriptional repression capacity is compromised. Conclusion: ROS induce expression of hypoxic COX5b and CYC7 genes through an Ord1- and Hap1-independent mechanism that promotes the release of Rox1 from or limits the access of Rox1 to its hypoxic gene promoter targets. Antioxid. Redox Signal. 19, 1916–1927.
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References
1.
Abramova NSertil OMehta SLowry CV. Reciprocal regulation of anaerobic and aerobic cell wall mannoprotein gene expression in Saccharomyces cerevisiaeJ Bacteriol1832881-28872001. 1. Abramova N, Sertil O, Mehta S, and Lowry, CV. Reciprocal regulation of anaerobic and aerobic cell wall mannoprotein gene expression in Saccharomyces cerevisiae. J Bacteriol 183: 2881–2887, 2001.
2.
Acker TAcker H. Cellular oxygen sensing need in CNS function: physiological and pathological implicationsJ Exp Biol2073171-31882004. 2. Acker T and Acker H. Cellular oxygen sensing need in CNS function: physiological and pathological implications. J Exp Biol 207: 3171–3188, 2004.
3.
Allen LAZhao XJCaughey WPoyton RO. Isoforms of yeast cytochrome c oxidase subunit V affect the binuclear reaction center and alter the kinetics of interaction with the isoforms of yeast cytochrome cJ Biol Chem270110-1181995. 3. Allen LA, Zhao XJ, Caughey W, and Poyton RO. Isoforms of yeast cytochrome c oxidase subunit V affect the binuclear reaction center and alter the kinetics of interaction with the isoforms of yeast cytochrome c. J Biol Chem 270: 110–118, 1995.
4.
Amberg DBurke DStrathern J. Chromatin immunoprecipitationMethods in Yeast Genetics: A Cold Spring Harbor Laboratory Course ManualAmberg DBurke DStrathern J.Woodbury, NYCold spring harbor laboratory press2005169-174. 4. Amberg D, Burke D, and Strathern J. Chromatin immunoprecipitation, In: Methods in Yeast Genetics: A Cold Spring Harbor Laboratory Course Manual, edited by Amberg D, Burke D, and Strathern J. Woodbury, NY: Cold spring harbor laboratory press, 2005, pp. 169–174.
5.
Ausubel FMBrent RKingston REMoore DDSeidman JGSmith JAStruhl K. Saccharomyces cerevisiaeCurrent Protocols in Molecular BiologyNew YorkWiley199413. 5. Ausubel FM, Brent R, Kingston RE, Moore DD, Seidman JG, Smith JA, and Struhl K. (Eds). Saccharomyces cerevisiae In: Current Protocols in Molecular Biology. New York: Wiley, 1994, p. 13.
6.
Balasubramanian BLowry CVZitomer RS. The Rox1 repressor of the Saccharomyces cerevisiae hypoxic genes is a specific DNA-binding protein with a high-mobility-group motifMol Cell Biol136071-60781993. 6. Balasubramanian B, Lowry CV, and Zitomer RS. The Rox1 repressor of the Saccharomyces cerevisiae hypoxic genes is a specific DNA-binding protein with a high-mobility-group motif. Mol Cell Biol 13: 6071–6078, 1993.
7.
Bell ELChandel NS. Mitochondrial oxygen sensing: regulation of hypoxia-inducible factor by mitochondrial generated reactive oxygen speciesEssays Biochem4317-272007. 7. Bell EL and Chandel NS. Mitochondrial oxygen sensing: regulation of hypoxia-inducible factor by mitochondrial generated reactive oxygen species. Essays Biochem 43: 17–27, 2007.
8.
Bourdineaud JPDe Sampaio GLauquin GJ. A Rox1-independent hypoxic pathway in yeast. Antagonistic action of the repressor Ord1 and activator Yap1 for hypoxic expression of the SRP1/TIR1 geneMol Microbiol38879-8902000. 8. Bourdineaud JP, De Sampaio G, and Lauquin GJ. A Rox1-independent hypoxic pathway in yeast. Antagonistic action of the repressor Ord1 and activator Yap1 for hypoxic expression of the SRP1/TIR1 gene. Mol Microbiol 38: 879–890, 2000.
9.
Burke PVRaitt DCAllen LAKellogg EAPoyton RO. Effects of oxygen concentration on the expression of cytochrome c and cytochrome c oxidase genes in yeastJ Biol Chem27214705-147121997. 9. Burke PV, Raitt DC, Allen LA, Kellogg EA, and Poyton RO. Effects of oxygen concentration on the expression of cytochrome c and cytochrome c oxidase genes in yeast. J Biol Chem 272: 14705–14712, 1997.
10.
Cadenas E. Biochemistry of oxygen toxicityAnnu Rev Biochem5879-1101989. 10. Cadenas E. Biochemistry of oxygen toxicity. Annu Rev Biochem 58: 79–110, 1989.
11.
Castello PRDavid PSMcClure TCrook ZPoyton RO. Mitochondrial cytochrome oxidase produces nitric oxide under hypoxic conditions: implications for oxygen sensing and hypoxic signaling in eukaryotesCell Metab3277-2872006. 11. Castello PR, David PS, McClure T, Crook Z, and Poyton RO. Mitochondrial cytochrome oxidase produces nitric oxide under hypoxic conditions: implications for oxygen sensing and hypoxic signaling in eukaryotes. Cell Metab 3: 277–287, 2006.
12.
Castro FAMariani DPanek ADEleutherio ECPereira MD. Cytotoxicity mechanism of two naphthoquinones (menadione and plumbagin) in Saccharomyces cerevisiaePLoS One3e39992008. 12. Castro FA, Mariani D, Panek AD, Eleutherio EC, and Pereira MD. Cytotoxicity mechanism of two naphthoquinones (menadione and plumbagin) in Saccharomyces cerevisiae. PLoS One 3: e3999, 2008.
13.
Castro-Prego RLamas-Maceiras MSoengas PCarneiro IGonzalez-Siso ICerdan ME. Regulatory factors controlling transcription of Saccharomyces cerevisiae IXR1 by oxygen levels: a model of transcriptional adaptation from aerobiosis to hypoxia implicating ROX1 and IXR1 cross-regulationBiochem J425235-2432009. 13. Castro-Prego R, Lamas-Maceiras M, Soengas P, Carneiro I, Gonzalez-Siso I, and Cerdan ME. Regulatory factors controlling transcription of Saccharomyces cerevisiae IXR1 by oxygen levels: a model of transcriptional adaptation from aerobiosis to hypoxia implicating ROX1 and IXR1 cross-regulation. Biochem J 425: 235–243, 2009.
14.
Clanton TL. Hypoxia-induced reactive oxygen species formation in skeletal muscleJ Appl Physiol1022379-23882007. 14. Clanton TL. Hypoxia-induced reactive oxygen species formation in skeletal muscle. J Appl Physiol 102: 2379–2388, 2007.
15.
Collins WRKirch ER. Determination and stability of menadioneJ Pharm Sci35215-2171946. 15. Collins WR and Kirch ER. Determination and stability of menadione. J Pharm Sci 35:215–217, 1946.
16.
Deckert JKhalaf RAHwang SMZitomer RS. Characterization of the DNA binding and bending HMG domain of the yeast hypoxic repressor Rox1Nucleic Acids Res273518-35261999. 16. Deckert J, Khalaf RA, Hwang SM, and Zitomer RS. Characterization of the DNA binding and bending HMG domain of the yeast hypoxic repressor Rox1. Nucleic Acids Res 27: 3518–3526, 1999.
17.
Di Flumeri CListon PAcheson NHKeng T. The HMG domain of the ROX1 protein mediates repression of HEM13 through overlapping DNA binding and oligomerization functionsNucleic Acids Res24808-8151996. 17. Di Flumeri C, Liston P, Acheson NH, and Keng T. The HMG domain of the ROX1 protein mediates repression of HEM13 through overlapping DNA binding and oligomerization functions. Nucleic Acids Res 24: 808–815, 1996.
18.
Dirmeier RO'Brien KMEngle MDodd ASpears EPoyton RO. Exposure of yeast cells to anoxia induces transient oxidative stress. Implications for the induction of hypoxic genesJ Biol Chem27734773-347842002. 18. Dirmeier R, O'Brien KM, Engle M, Dodd A, Spears E, and Poyton RO. Exposure of yeast cells to anoxia induces transient oxidative stress. Implications for the induction of hypoxic genes. J Biol Chem 277: 34773–34784, 2002.
19.
Fontanesi FSoto ICHorn DBarrientos A. Assembly of mitochondrial cytochrome c oxidase, a complicated and highly regulated cellular processAm J Physiol Cell Physiol291C1129-C11472006. 19. Fontanesi F, Soto IC, Horn D, and Barrientos A. Assembly of mitochondrial cytochrome c oxidase, a complicated and highly regulated cellular process. Am J Physiol Cell Physiol 291: C1129– C1147, 2006.
20.
Fukuda RZhang HKim JWShimoda LDang CVSemenza GL. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cellsCell129111-1222007. 20. Fukuda R, Zhang H, Kim JW, Shimoda L, Dang CV, and Semenza, GL. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell 129: 111–122, 2007.
21.
Gasch APSpellman PTKao CMCarmel-Harel OEisen MBStorz GBotstein DBrown PO. Genomic expression programs in the response of yeast cells to environmental changesMol Biol Cell114241-42572000. 21. Gasch AP, Spellman PT, Kao CM, Carmel-Harel O, Eisen MB, Storz G, Botstein D, and Brown PO. Genomic expression programs in the response of yeast cells to environmental changes. Mol Biol Cell 11: 4241–4257, 2000.
22.
Guzy RDHoyos BRobin EChen HLiu LMansfield KDSimon MCHammerling USchumacker PT. Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensingCell Metab1401-4082005. 22. Guzy RD, Hoyos B, Robin E, Chen H, Liu L, Mansfield KD, Simon MC, Hammerling U, and Schumacker PT. Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab 1: 401–408, 2005.
23.
Guzy RDMack MMSchumacker PT. Mitochondrial complex III is required for hypoxia-induced ROS production and gene transcription in yeastAntioxid Redox Signal91317-13282007. 23. Guzy RD, Mack MM, and Schumacker PT. Mitochondrial complex III is required for hypoxia-induced ROS production and gene transcription in yeast. Antioxid Redox Signal 9: 1317–1328, 2007.
24.
Guzy RDSchumacker PT. Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxiaExp Physiol91807-8192006. 24. Guzy RD and Schumacker PT. Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia. Exp Physiol 91: 807–819, 2006.
25.
Hodge MRKim GSingh KCumsky MG. Inverse regulation of the yeast COX5 genes by oxygen and hemeMol Cell Biol91958-19641989. 25. Hodge MR, Kim G, Singh K, and Cumsky MG. Inverse regulation of the yeast COX5 genes by oxygen and heme. Mol Cell Biol 9: 1958–1964, 1989.
26.
Hodge MRSingh KCumsky MG. Upstream activation and repression elements control transcription of the yeast COX5b geneMol Cell Biol105510-55201990. 26. Hodge MR, Singh K, and Cumsky MG. Upstream activation and repression elements control transcription of the yeast COX5b gene. Mol Cell Biol 10: 5510–5520, 1990.
27.
Klimova TChandel NS. Mitochondrial complex III regulates hypoxic activation of HIFCell Death Differ15660-6662008. 27. Klimova T and Chandel NS. Mitochondrial complex III regulates hypoxic activation of HIF. Cell Death Differ 15: 660–666, 2008.
28.
Kwast KEBurke PVStaahl BTPoyton RORaitt DCAllen LAKellogg EA. Oxygen sensing in yeast: evidence for the involvement of the respiratory chain in regulating the transcription of a subset of hypoxic genesProc Natl Acad Sci U S A965446-54511999. 28. Kwast KE, Burke PV, Staahl BT, Poyton RO, Raitt DC, Allen LA, and Kellogg EA. Oxygen sensing in yeast: evidence for the involvement of the respiratory chain in regulating the transcription of a subset of hypoxic genes. Proc Natl Acad Sci U S A 96: 5446–5451, 1999.
29.
Lambert JRBilanchone VWCumsky MG. The ORD1 gene encodes a transcription factor involved in oxygen regulation and is identical to IXR1, a gene that confers cisplatin sensitivity to Saccharomyces cerevisiaeProc Natl Acad Sci U S A917345-73491994. 29. Lambert JR, Bilanchone VW, and Cumsky MG. The ORD1 gene encodes a transcription factor involved in oxygen regulation and is identical to IXR1, a gene that confers cisplatin sensitivity to Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 91: 7345–7349, 1994.
30.
Lowry CVCerdan MEZitomer RS. A hypoxic consensus operator and a constitutive activation region regulate the ANB1 gene of Saccharomyces cerevisiaeMol Cell Biol105921-59261990. 30. Lowry CV, Cerdan ME, and Zitomer RS. A hypoxic consensus operator and a constitutive activation region regulate the ANB1 gene of Saccharomyces cerevisiae. Mol Cell Biol 10: 5921–5926, 1990.
31.
Lowry CVZitomer RS. ROX1 encodes a heme-induced repression factor regulating ANB1 and CYC7 of Saccharomyces cerevisiaeMol Cell Biol84651-46581988. 31. Lowry CV and Zitomer RS. ROX1 encodes a heme-induced repression factor regulating ANB1 and CYC7 of Saccharomyces cerevisiae. Mol Cell Biol 8: 4651–4658, 1988.
32.
McA'Nulty MMWhitehead JPLippard SJ. Binding of Ixr1, a yeast HMG-domain protein, to cisplatin-DNA adducts in vitro and in vivoBiochemistry356089-60991996. 32. McA'Nulty MM, Whitehead JP, and Lippard SJ. Binding of Ixr1, a yeast HMG-domain protein, to cisplatin-DNA adducts in vitro and in vivo. Biochemistry 35: 6089–6099, 1996.
33.
Mennella TAKlinkenberg LGZitomer RS. Recruitment of Tup1-Ssn6 by yeast hypoxic genes and chromatin-independent exclusion of TATA binding proteinEukaryot Cell21288-13032003. 33. Mennella TA, Klinkenberg LG, and Zitomer RS. Recruitment of Tup1-Ssn6 by yeast hypoxic genes and chromatin-independent exclusion of TATA binding protein. Eukaryot Cell 2: 1288–1303, 2003.
34.
Montanes FMPascual-Ahuir AProft M. Repression of ergosterol biosynthesis is essential for stress resistance and is mediated by the Hog1 MAP kinase and the Mot3 and Rox1 transcription factorsMol Microbiol791008-10232011. 34. Montanes FM, Pascual-Ahuir A, and Proft M. Repression of ergosterol biosynthesis is essential for stress resistance and is mediated by the Hog1 MAP kinase and the Mot3 and Rox1 transcription factors. Mol Microbiol 79: 1008–1023, 2011.
35.
Paget MSButtner MJ. Thiol-based regulatory switchesAnnu Rev Genet3791-1212003. 35. Paget MS and Buttner MJ. Thiol-based regulatory switches. Annu Rev Genet 37: 91–121, 2003.
36.
Patten DALafleur VNRobitaille GAChan DAGiaccia AJRichard DE. Hypoxia-inducible factor-1 activation in nonhypoxic conditions: the essential role of mitochondrial-derived reactive oxygen speciesMol Cell213247-32572010. 36. Patten DA, Lafleur VN, Robitaille GA, Chan DA, Giaccia AJ, and Richard DE. Hypoxia-inducible factor-1 activation in nonhypoxic conditions: the essential role of mitochondrial-derived reactive oxygen species. Mol Cell 21: 3247–3257, 2010.
37.
Poyton RO. Models for oxygen sensing in yeast: implications for oxygen-regulated gene expression in higher eucaryotesRespir Physiol115119-1331999. 37. Poyton RO. Models for oxygen sensing in yeast: implications for oxygen-regulated gene expression in higher eucaryotes. Respir Physiol 115: 119–133, 1999.
38.
Poyton ROBall KACastello PR. Mitochondrial generation of free radicals and hypoxic signalingTrends Endocrinol Metab20332-3402009. 38. Poyton RO, Ball KA, and Castello PR. Mitochondrial generation of free radicals and hypoxic signaling. Trends Endocrinol Metab 20: 332–340, 2009.
39.
Rodrigues-Pousada CMenezes RAPimentel C. The Yap family and its role in stress responseYeast27245-2582010. 39. Rodrigues-Pousada C, Menezes RA, and Pimentel C. The Yap family and its role in stress response. Yeast 27: 245–258, 2010.
40.
Smith RLJohnson AD. Turning genes off by Ssn6-Tup1: a conserved system of transcriptional repression in eukaryotesTrends Biochem Sci25325-3302000. 40. Smith RL and Johnson AD. Turning genes off by Ssn6-Tup1: a conserved system of transcriptional repression in eukaryotes. Trends Biochem Sci 25: 325–330, 2000.
41.
Solans AZambrano ARodriguez MBarrientos A. Cytotoxicity of a mutant huntingtin fragment in yeast involves early alterations in mitochondrial OXPHOS complexes II and IIIHum Mol Genet153063-30812006. 41. Solans A, Zambrano A, Rodriguez M, and Barrientos A. Cytotoxicity of a mutant huntingtin fragment in yeast involves early alterations in mitochondrial OXPHOS complexes II and III. Hum Mol Genet 15: 3063–3081, 2006.
42.
Sundar IKCaito SYao HRahman I. Oxidative stress, thiol redox signaling methods in epigeneticsMethods Enzymol474213-2442010. 42. Sundar IK, Caito S, Yao H, and Rahman, I. Oxidative stress, thiol redox signaling methods in epigenetics. Methods Enzymol 474: 213–244, 2010.
43.
Trueblood CEPoyton RO. Identification of REO1, a gene involved in negative regulation of COX5b and ANB1 in aerobically grown Saccharomyces cerevisiaeGenetics120671-6801988. 43. Trueblood CE and Poyton RO. Identification of REO1, a gene involved in negative regulation of COX5b and ANB1 in aerobically grown Saccharomyces cerevisiae. Genetics 120: 671–680, 1988.
44.
Waterland RABasu AChance BPoyton RO. The isoforms of yeast cytochrome c oxidase subunit V alter the in vivo kinetic properties of the holoenzymeJ Biol Chem2664180-41861991. 44. Waterland RA, Basu A, Chance B, and Poyton RO. The isoforms of yeast cytochrome c oxidase subunit V alter the in vivo kinetic properties of the holoenzyme. J Biol Chem 266: 4180–4186, 1991.
45.
Zitomer RSLowry CV. Regulation of gene expression by oxygen in Saccharomyces cerevisiaeMicrobiol Rev561-111992. 45. Zitomer RS and Lowry, CV. Regulation of gene expression by oxygen in Saccharomyces cerevisiae. Microbiol Rev 56: 1–11, 1992.
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Published In
Antioxidants & Redox Signaling
Volume 19 • Issue Number 16 • December 1, 2013
Pages: 1916 - 1927
PubMed: 22703342
Copyright
Copyright 2013, Mary Ann Liebert, Inc.
History
Published in print: December 1, 2013
Published online: 26 November 2013
Published ahead of print: 6 August 2012
Published ahead of production: 15 June 2012
Accepted: 15 June 2012
Revision received: 2 June 2012
Received: 28 February 2012
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