A Heterodimer of the Zn2Cys6 Transcription Factors Pip2p and Oaf1p Controls Induction of Genes Encoding Peroxisomal Proteins in Saccharomyces Cerevisiae

Rottensteiner, Hanspeter; Kal, Arnoud J.; Hamilton, Barbara; Ruis, Helmut; Tabak, Henk F.

doi:10.1111/j.1432-1033.1997.00776.x

Cited by 114 publications

(134 citation statements)

References 52 publications

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“…4C and D), indicating structural integrity. This finding is consistent with the fact that Oaf1͞Pip2 heterodimers can form and bind DNA in the absence of oleate (17)(18)(19).…”

Section: Spectrum Of In Vivosupporting

confidence: 79%

“…Oaf1 and Pip2 are essential heterodimeric transcription factors for the utilization of the fatty acid oleate as an external carbon source (17)(18)(19)(20). In the absence of glucose, the preferred carbon source of S. cerevisiae, oleate induces the expression of the entire panel of genes required for uptake and breakdown of fatty acids in an OAF1͞PIP2-dependent fashion (18)(19)(20)(21). Moreover, the transcriptional activity of Oaf1 fused to a heterologous DBD is stimulated by oleate (22).…”

Section: Spectrum Of In Vivomentioning

confidence: 99%

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Fungi and animals may share a common ancestor to nuclear receptors

Phelps

Gburcik

Suslova

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Nuclear receptors (NRs) are a large family of transcription factors. One hallmark of this family is the ligand-binding domain (LBD), for its primary sequence, structure, and regulatory function. To date, NRs have been found exclusively in animals and sponges, which has led to the generally accepted notion that they arose with them. We have overcome the limitations of primary sequence searches by combining sequence profile searches with structural predictions at a genomic scale, and have discovered that the heterodimeric transcription factors Oaf1͞Pip2 of the budding yeast Saccharomyces cerevisiae contain putative LBDs resembling those of animal NRs. Although the Oaf1͞Pip2 LBDs are embedded in an entirely different architecture, the regulation and function of these transcription factors are strikingly similar to those of the mammalian NR heterodimer peroxisome proliferator-activated receptor ␣͞ret-inoid X receptor (PPAR␣͞RXR). We demonstrate that the induction of Oaf1͞Pip2 activity by the fatty acid oleate depends on oleate's direct binding to the Oaf1 LBD. The alteration of two amino acids in the predicted ligand-binding pocket of Oaf1 abolishes both ligand binding and the transcriptional response. Hence, LBDs may have arisen as allosteric switches, for example, to respond to nutritional and metabolic ligands, before the animal and fungal lineages diverged.evolution ͉ fatty acids ͉ structure prediction ͉ yeast ͉ bioinformatics T he nuclear receptor (NR) superfamily is characterized by two unique domains. Almost all members contain a very highly conserved DNA-binding domain (DBD) consisting of two Cys 4 zinc fingers, as well as a somewhat less conserved ligand-binding domain (LBD) comprising Ϸ250 aa at the C terminus. These building blocks confer the potential to act as both an intracellular receptor and a ligand-regulated transcription factor. Although only a minority of NRs have known ligands, it appears that LBDs evolved as allosteric switches to control NR activities as transcription factors (1-3).Homologous sequences have been identified in a large number of species by performing searches with DBD and͞or LBD sequences (3, 4). Because only animals and sponges have recognizable NR sequences, it has been concluded that NRs evolved in a common animal or urmetazoan ancestor (5, 6). However, because these primary sequence searches were all based on one of the available BLAST algorithms (7,8), more distant homologs with poor primary sequence similarity could not have been identified. We have now combined such searches with structural predictions and have uncovered additional potential homologs in yeast. Our results challenge the assumption that NRs are an animal-specific family of transcription factors and argue that allosteric regulation by NR LBDs is more ancient than animals.

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“…4C and D), indicating structural integrity. This finding is consistent with the fact that Oaf1͞Pip2 heterodimers can form and bind DNA in the absence of oleate (17)(18)(19).…”

Section: Spectrum Of In Vivosupporting

confidence: 79%

Section: Spectrum Of In Vivomentioning

confidence: 99%

Fungi and animals may share a common ancestor to nuclear receptors

Phelps

Gburcik

Suslova

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Such heterodimers would be impaired for activation of the PDR5 gene. In support of this model, zinc cluster proteins Oaf1 and Pip2p, involved in activation of peroxisomal genes, have been shown to bind to DNA as heterodimers (45). Ada3p, a subunit of the SAGA complex involved in chromatin remodeling, represses activity of Pdr1p (46).…”

Section: Rdr1p Is a Repressor Of Pdr5 Expressionmentioning

confidence: 99%

Zinc Cluster Protein Rdr1p Is a Transcriptional Repressor of the PDR5 Gene Encoding a Multidrug Transporter

Hellauer¹,

Akache²,

MacPherson³

et al. 2002

Journal of Biological Chemistry

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The yeast PDR5 gene encodes an efflux pump that confers multidrug resistance. Expression of PDR5 is positively regulated by the transcription factors Pdr1p and Pdr3p that recognize the same pleiotropic drug resistance elements (PDREs) in the PDR5 promoter. Pdr1p and Pdr3p belong to the Gal4p family of zinc cluster proteins. The function of RDR1 (YOR380W), which also encodes a member of this family, is unknown. To identify target genes for Rdr1p, we have performed wholegenome analysis of gene expression with DNA microarrays. Our results show that Rdr1p is a transcriptional repressor of five genes, including PDR5. A ⌬rdr1 strain has increased resistance to cycloheximide, as expected from the overexpression of PDR5. In addition, the activity of a PDR5-lacZ reporter is increased in a ⌬rdr1 strain. All (but one) genes affected by removal of Rdr1p contain PDREs in their promoters. We tested if the effect of Rdr1p is mediated through PDREs by inserting this DNA element in front of a minimal promoter. Activity of this reporter was increased in a ⌬rdr1 strain. Moreover, mutations known to reduce binding of Pdr1/ Pdr3p abolished the induction observed in the ⌬rdr1 strain. Thus, we have identified a transcriptional repressor involved in the control of multidrug resistance.Multidrug resistance is a widespread phenomenon that allows organisms ranging from bacteria to humans to defend themselves against a variety of toxic compounds. Drug resistance is mediated through membrane-bound transporters that act as drug efflux pumps. This process has been extensively studied in the yeast Saccharomyces cerevisiae. Two major classes of multidrug transporters have been identified: the major facilitator superfamily (MFS) 1 (1) and the ABC (ATP binding cassette) family of transporters (2-4). ABC transporters act in an ATP-dependent manner, and their overexpression leads to increased drug resistance. Members of the family of ABC transporters include Pdr5p, Snq2p, and Yor1p (2).The transcriptional activators Pdr1p and Pdr3p control the expression of many ABC transporters (3, 4). These activators belong to a family of transcriptional regulators called zinc cluster or binuclear cluster proteins (5-7). Members of this family contain six highly conserved cysteines that coordinate binding to two zinc atoms to allow proper folding of the DNA binding domain. The cysteine-rich region (or zinc finger) is usually followed by a short linker sequence that bridges the zinc finger to a dimerization domain (6). This domain is involved in recognition of specific DNA sequences through interaction of the zinc finger with DNA (for references see Ref. 8). Pdr1p and Pdr3p both recognize CGG triplets oriented in opposite directions (CCGCGG) to form an everted repeat (9). This motif is found in the target genes of Pdr1p and Pdr3p (10 -17). For example, three binding sites called PDREs (pleiotropic drug response elements) for Pdr1p and Pdr3p have been mapped in the PDR5 promoter (10, 12). Thus, Pdr1p and Pdr3p recognize the same DNA sequences in target promoters f...

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“…OAF1 is expressed constitutively, whereas expression of PIP2 is regulated (58). The heterodimeric Oaf1-Pip2 transcription factor is active only in the presence of an inducing fatty acid such as oleate.…”

Section: Figmentioning

confidence: 99%

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

Young¹,

Dombek²,

Tachibana

et al. 2003

Journal of Biological Chemistry

255

310

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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 acetylCoA 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.During the diauxic shift, when yeast cells deplete the glucose in the medium, the flow of metabolites changes dramatically to adapt to the use of alternative energy and carbon sources, primarily ethanol produced during fermentation. The changes in gene expression that are required for this metabolic reorganization were dramatically revealed by DNA microarray analysis (1). The expression of more than one-quarter of the yeast genome is altered when glucose is exhausted. These alterations allow the cell to utilize carbon sources other than glucose to channel metabolites into the tricarboxylic acid and glyoxylate cycles to generate energy and synthesize intermediates for gluconeogenesis. In addition, these changes allow the cell to alter its growth rate and prepare for growth arrest and stationary phase.Numerous transcription factors and regulatory proteins are responsible for the altered transcriptional program that accompanies the depletion of glucose. Two transcription factors that play important roles during the diauxic transition are Adr1 1 and Cat8.

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A Heterodimer of the Zn₂Cys₆ Transcription Factors Pip2p and Oaf1p Controls Induction of Genes Encoding Peroxisomal Proteins in Saccharomyces Cerevisiae

Cited by 114 publications

References 52 publications

Fungi and animals may share a common ancestor to nuclear receptors

Fungi and animals may share a common ancestor to nuclear receptors

Zinc Cluster Protein Rdr1p Is a Transcriptional Repressor of the PDR5 Gene Encoding a Multidrug Transporter

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

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