Multiple Pathways Are Co-regulated by the Protein Kinase Snf1 and the Transcription Factors Adr1 and Cat8*

ADR1 and CAT8 encode carbon source-responsive transcriptional regulators that cooperatively control expression of genes involved in ethanol utilization. These transcription factors are active only after the diauxic transition, when glucose is depleted and energy-generating metabolism has shifted to the aerobic oxidation of non-fermentable carbon sources. The Snf1 protein kinase complex is required for activation of their downstream target genes described previously. Using DNA microarrays, we determined the extent to which these three factors collaborate in regulating the expression of the yeast genome after glucose depletion. The expression of 108 genes is significantly decreased in the absence of ADR1. The importance of ADR1 during the diauxic transition is illustrated by the observation that expression of almost one-half of the 40 most highly glucose-repressed genes is ADR1-dependent. ADR1-dependent genes fall into a variety of functional classes with carbon metabolism containing the largest number of members. Most of the genes in this class are involved in the oxidation of different non-fermentable carbon sources. These microarray data show that ADR1 coordinates the biochemical pathways that generate acetyl-CoA and NADH from non-fermentable substrates. Only a small number of ADR1-dependent genes are also CAT8-dependent. However, nearly one-half of the ADR1-dependent genes are also dependent on the Snf1 protein kinase for derepression. Many more genes are SNF1-dependent than are either ADR1- or CAT8-dependent suggesting that SNF1 plays a broader role in gene expression than either ADR1 or CAT8. The largest class of SNF1-dependent genes encodes regulatory proteins that could extend SNF1 dependence to additional pathways.

[1]  H J Schüller,et al.  Transcriptional control of the yeast acetyl‐CoA synthetase gene, ACS1, by the positive regulators CAT8 and ADR1 and the pleiotropic repressor UME6 , 1997, Molecular microbiology.

[2]  M. G. Koerkamp,et al.  Dynamics of gene expression revealed by comparison of serial analysis of gene expression transcript profiles from yeast grown on two different carbon sources. , 1999, Molecular biology of the cell.

[3]  K. Entian,et al.  CAT8, a new zinc cluster-encoding gene necessary for derepression of gluconeogenic enzymes in the yeast Saccharomyces cerevisiae , 1995, Molecular and cellular biology.

[4]  H. Blumberg,et al.  Sequence homology of the yeast regulatory protein ADR1 with Xenopus transcription factor TFIIIA , 1986, Nature.

[5]  H. Tabak,et al.  Pip2p: a transcriptional regulator of peroxisome proliferation in the yeast Saccharomyces cerevisiae. , 1996, The EMBO journal.

[6]  P. Brown,et al.  Exploring the metabolic and genetic control of gene expression on a genomic scale. , 1997, Science.

[7]  K. Entian,et al.  Glucose derepression of gluconeogenic enzymes in Saccharomyces cerevisiae correlates with phosphorylation of the gene activator Cat8p , 1997, Molecular and cellular biology.

[8]  Thomas Fiedler,et al.  A new efficient gene disruption cassette for repeated use in budding yeast , 1996, Nucleic Acids Res..

[9]  M. Carlson,et al.  Interaction of the repressors Nrg1 and Nrg2 with the Snf1 protein kinase in Saccharomyces cerevisiae. , 2001, Genetics.

[10]  K. Arndt,et al.  Evidence for the involvement of the Glc7-Reg1 phosphatase and the Snf1-Snf4 kinase in the regulation of INO1 transcription in Saccharomyces cerevisiae. , 1999, Genetics.

[11]  J. Collado-Vides,et al.  A web site for the computational analysis of yeast regulatory sequences , 2000, Yeast.

[12]  G. Fink,et al.  Combinatorial Control Required for the Specificity of Yeast MAPK Signaling , 1997, Science.

[13]  P. Pavlík,et al.  The glycerol kinase (GUT1) gene of Saccharomyces cerevisiae: cloning and characterization , 1993, Current Genetics.

[14]  H. Schüller,et al.  Contribution of Cat8 and Sip4 to the transcriptional activation of yeast gluconeogenic genes by carbon source-responsive elements , 2001, Current Genetics.

[15]  M. Carlson,et al.  Yeast SNF1 protein kinase interacts with SIP4, a C6 zinc cluster transcriptional activator: a new role for SNF1 in the glucose response , 1996, Molecular and cellular biology.

[16]  G. Adam,et al.  Control of peroxisome proliferation in Saccharomyces cerevisiae by ADR1, SNF1 (CAT1, CCR1) and SNF4 (CAT3) , 1992, Yeast.

[17]  M. Perrot,et al.  The Transcriptional Activator Cat8p Provides a Major Contribution to the Reprogramming of Carbon Metabolism during the Diauxic Shift inSaccharomyces cerevisiae * , 2001, The Journal of Biological Chemistry.

[18]  S. Berger,et al.  Snf1--a Histone Kinase That Works in Concert with the Histone Acetyltransferase Gcn5 to Regulate Transcription , 2001, Science.

[19]  Saeed Tavazoie,et al.  Genome-wide binding map of the histone deacetylase Rpd3 in yeast , 2002, Nature Genetics.

[20]  M. Ciriacy,et al.  Isolation and characterization of further Cis- and Trans-acting regulatory elements involved in the synthesis of glucose-repressible alcohol dehydrogenase (ADHII) in Saccharomyces cerevisiae , 1979, Molecular and General Genetics MGG.

[21]  K. Walther,et al.  Adr1 and Cat8 synergistically activate the glucose-regulated alcohol dehydrogenase gene ADH2 of the yeast Saccharomyces cerevisiae. , 2001, Microbiology.

[22]  V. Plakunov,et al.  Antagonistic Interactions between Stress Factors during the Growth of Microorganisms under Conditions Simulating the Parameters of Their Natural Ecotopes , 2002, Microbiology.

[23]  J. Hiltunen,et al.  Saccharomyces cerevisiae Adr1p Governs Fatty Acid β-Oxidation and Peroxisome Proliferation by RegulatingPOX1 and PEX11 * , 2001, The Journal of Biological Chemistry.

[24]  J. Pronk,et al.  Functional analysis of structural genes for NAD+‐dependent formate dehydrogenase in Saccharomyces cerevisiae , 2002, Yeast.

[25]  Trey Ideker,et al.  Transcriptome profiling to identify genes involved in peroxisome assembly and function , 2002, The Journal of cell biology.

[26]  M. Grunstein,et al.  Hyperacetylation of chromatin at the ADH2 promoter allows Adr1 to bind in repressed conditions , 2002, The EMBO journal.

[27]  A. Steinbüchel,et al.  The methylcitric acid pathway in Ralstonia eutropha: new genes identified involved in propionate metabolism. , 2001, Microbiology.

[28]  W. Kunau,et al.  Peroxisome biogenesis inSaccharomyces cerevisiae , 1992, Antonie van Leeuwenhoek.

[29]  C. Denis The effects of ADR1 and CCR1 gene dosage on the regulation of the glucose-repressible alcohol dehydrogenase from Saccharomyces cerevisiae , 1987, Molecular and General Genetics MGG.

[30]  M. G. Koerkamp,et al.  Dissection of transient oxidative stress response in Saccharomyces cerevisiae by using DNA microarrays. , 2002, Molecular biology of the cell.

[31]  M. Johnston,et al.  Regulated nuclear translocation of the Mig1 glucose repressor. , 1997, Molecular biology of the cell.

[32]  J. Lopes,et al.  Expression of GUT1, which encodes glycerol kinase in Saccharomyces cerevisiae, is controlled by the positive regulators Adr1p, Ino2p and Ino4p and the negative regulator Opi1p in a carbon source-dependent fashion. , 1999, Nucleic acids research.

[33]  S. Henry,et al.  The REG1 gene product is required for repression of INO1 and other inositol-sensitive upstream activating sequence-containing genes of yeast. , 1999, Genetics.

[34]  J. Pronk,et al.  The Saccharomyces cerevisiae ICL2 Gene Encodes a Mitochondrial 2-Methylisocitrate Lyase Involved in Propionyl-Coenzyme A Metabolism , 2000, Journal of bacteriology.

[35]  H. Ruis,et al.  Adr1p-dependent regulation of the oleic acid-inducible yeast gene SPS19 encoding the peroxisomal beta-oxidation auxiliary enzyme 2,4-dienoyl-CoA reductase. , 2000, Molecular cell biology research communications : MCBRC.

[36]  J. Yu,et al.  Adjacent upstream activation sequence elements synergistically regulate transcription of ADH2 in Saccharomyces cerevisiae , 1989, Molecular and cellular biology.

[37]  D. Fraenkel Genetics and intermediary metabolism. , 1992, Annual review of genetics.

[38]  D. Thiele,et al.  Identification and analysis of a Saccharomyces cerevisiae copper homeostasis gene encoding a homeodomain protein , 1994, Molecular and cellular biology.

[39]  B Hamilton,et al.  A heterodimer of the Zn2Cys6 transcription factors Pip2p and Oaf1p controls induction of genes encoding peroxisomal proteins in Saccharomyces cerevisiae. , 1997, European journal of biochemistry.

[40]  M. Carlson,et al.  Sip4, a Snf1 kinase‐dependent transcriptional activator, binds to the carbon source‐responsive element of gluconeogenic genes , 1998, The EMBO journal.

[41]  Nicola J. Rinaldi,et al.  Transcriptional Regulatory Networks in Saccharomyces cerevisiae , 2002, Science.

[42]  P. J. Trotter,et al.  The genetics of fatty acid metabolism in Saccharomyces cerevisiae. , 2001, Annual review of nutrition.

[43]  E. Young,et al.  Snf1 Protein Kinase Regulates Adr1 Binding to Chromatin but Not Transcription Activation* , 2002, The Journal of Biological Chemistry.

[44]  P. Slonimski,et al.  Functional analysis of RRD1 (YIL153w) and RRD2 (YPL152w), which encode two putative activators of the phosphotyrosyl phosphatase activity of PP2A in Saccharomyces cerevisiae , 2000, Molecular and General Genetics MGG.

[45]  S. Henry,et al.  Inhibition of Acetyl Coenzyme A Carboxylase Activity Restores Expression of the INO1 Gene in a snf1Mutant Strain of Saccharomyces cerevisiae , 2001, Molecular and Cellular Biology.

[46]  D. Valle,et al.  A Saccharomyces cerevisiae homolog of the human adrenoleukodystrophy transporter is a heterodimer of two half ATP-binding cassette transporters. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[47]  M. Carlson,et al.  Glucose repression in yeast. , 1999, Current opinion in microbiology.

[48]  B. Bainbridge,et al.  Genetics , 1981, Experientia.

[49]  G. Adam,et al.  The Saccharomyces cerevisiae ADR1 gene is a positive regulator of transcription of genes encoding peroxisomal proteins , 1991, Molecular and cellular biology.

[50]  J. François,et al.  Deletion of SNF1 affects the nutrient response of yeast and resembles mutations which activate the adenylate cyclase pathway. , 1991, Genetics.

[51]  K. M. Dombek,et al.  ADH2 expression is repressed by REG1 independently of mutations that alter the phosphorylation of the yeast transcription factor ADR1 , 1993, Molecular and cellular biology.

[52]  S. Eykyn Microbiology , 1950, The Lancet.

[53]  W. A. Scheffers,et al.  Propionate metabolism in Saccharomyces cerevisiae: implications for the metabolon hypothesis. , 1994, Microbiology.

[54]  K. Tatchell,et al.  Protein phosphatase type 1 regulates ion homeostasis in Saccharomyces cerevisiae. , 2002, Genetics.

[55]  B. Guiard,et al.  Regulation of the CYB2 gene expression: transcriptional co‐ordination by the Hap1p, Hap2/3/4/5p and Adr1p transcription factors , 2000, Molecular microbiology.

[56]  Trey Ideker,et al.  Testing for Differentially-Expressed Genes by Maximum-Likelihood Analysis of Microarray Data , 2000, J. Comput. Biol..

[57]  宁北芳,et al.  疟原虫var基因转换速率变化导致抗原变异[英]/Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A , 2005 .

[58]  S. Thukral,et al.  Mutations in the zinc fingers of ADR1 that change the specificity of DNA binding and transactivation , 1992, Molecular and cellular biology.

[59]  Varshal K. Davé,et al.  Genome-wide responses to mitochondrial dysfunction. , 2001, Molecular biology of the cell.

[60]  K. M. Dombek,et al.  Characterization of a p53-related Activation Domain in Adr1p That Is Sufficient for ADR1-dependent Gene Expression* , 1998, The Journal of Biological Chemistry.

[61]  K. M. Dombek,et al.  Post-translational Regulation of Adr1 Activity Is Mediated by Its DNA Binding Domain* , 1999, The Journal of Biological Chemistry.

[62]  M. Carlson,et al.  Snf1 Protein Kinase Regulates Phosphorylation of the Mig1 Repressor in Saccharomyces cerevisiae , 1998, Molecular and Cellular Biology.

[63]  K. M. Dombek,et al.  Identification of potential target genes for Adr1p through characterization of essential nucleotides in UAS1 , 1994, Molecular and cellular biology.

[64]  L. Guarente Yeast promoters and lacZ fusions designed to study expression of cloned genes in yeast. , 1983, Methods in enzymology.

[65]  Amir Sherman,et al.  Multiple and Distinct Activation and Repression Sequences Mediate the Regulated Transcription of IME1, a Transcriptional Activator of Meiosis-Specific Genes inSaccharomyces cerevisiae , 1998, Molecular and Cellular Biology.