Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.3.3.1 (citrate synthase)
 4,488 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of some nuclear genes is sensitive to the functional state of mitochondria, a process we term retrograde regulation. Here we show that retrograde regulation of the yeast CIT2 gene encoding peroxisomal citrate synthase depends on a new class of upstream activation site element (UASr) and two previously unidentified genes, RTG1 and RTG2. RTG1 encodes a protein of 177 amino acids with similarity to basic helix-loop-helix transcription factors that likely functions at the CIT2 UASr. RTG2 encodes a protein of 394 amino acids of unknown function. Cells containing null alleles of RTG1 and RTG2 are viable and respiratory competent. However, they are auxotrophic for glutamic or aspartic acid and cannot use acetate as a sole carbon source, suggesting that both the tricarboxylic acid and glyoxylate cycles are compromised. Thus, RTG1 and RTG2 are pivotal genes in controlling interorganelle communication between mitochondria, peroxisomes, and the nucleus.
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PMID:RTG1 and RTG2: two yeast genes required for a novel path of communication from mitochondria to the nucleus. 842 83

The expression of some nuclear genes in Saccharomyces cerevisiae, such as the CIT2 gene, which encodes a glyoxylate cycle isoform of citrate synthase, is responsive to the functional state of mitochondria. Previous studies identified a basic helix-loop-helix-leucine zipper (bHLH/Zip) transcription factor encoded by the RTG1 gene that is required for both basal expression of the CIT2 gene and its increased expression in respiratory-deficient cells. Here, we describe the cloning and characterization of RTG3, a gene encoding a 54-kDa bHLH/Zip protein that is also required for CIT2 expression. Rtg3p binds together with Rtg1p to two identical sites oriented as inverted repeats 28 bp apart in a regulatory upstream activation sequence element (UASr) in the CIT2 promoter. The core binding site for the Rtg1p-Rtg3p heterodimer is 5'-GGTCAC-3', which differs from the canonical E-box site, CANNTG, to which most other bHLH proteins bind. We demonstrate that both of the Rtg1p-Rtg3p binding sites in the UAS(r) element are required in vivo and act synergistically for CIT2 expression. The basic region of Rtg3p conforms well to the basic region of most bHLH proteins, whereas the basic region of Rtg1p does not. These findings suggest that the Rtg1p-Rtg3p complex interacts in a novel way with its DNA target sites.
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PMID:A basic helix-loop-helix-leucine zipper transcription complex in yeast functions in a signaling pathway from mitochondria to the nucleus. 903 38

Rtg3p and Rtg1p are basic helix-loop-helix/leucine zipper protein transcription factors in yeast that interact and bind to sites in an upstream activation sequence element in the 5'-flanking region of CIT2, a gene encoding a peroxisomal isoform of citrate synthase. These factors are required both for basal expression of CIT2 and its elevated expression in cells with dysfunctional mitochondria, such as in respiratory-deficient petite cells lacking mitochondrial DNA (rho degrees ). This elevated expression of CIT2 is called the retrograde response. Here we show that fusion constructs between the Gal4p DNA binding domain and Rtg3p transactivate the expression of a LacZ reporter gene under the control of a GAL1 promoter element. We have identified two activation domains in Rtg3p: a strong carboxyl-terminal domain from amino acids 375-486, and a weaker amino-terminal domain from amino acids 1-175; neither of these activation domains contain the bHLH/Zip motif. We have also identified a serine/threonine-rich domain of Rtg3p within amino acids 176-282 that is inhibitory to transactivation. In addition, the transcriptional activity of the Gal4-Rtg3p fusion proteins does not require either Rtg1p or Rtg2p; the latter is a protein containing an hsp70-like ATP binding domain that is also necessary for CIT2 expression. In contrast, transcriptional activation by Gal4-Rtg1p fusion proteins requires the Rtg1p basic helix-loop-helix/leucine zipper protein domain, as well as Rtg3p and Rtg2p. These data suggest that transcriptional activation by the Rtg1p-Rtg3p complex is largely the function of Rtg3p. Experiments are also presented suggesting that Rtg3p is limiting for gene expression in respiratory-competent (rho+) cells.
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PMID:Rtg3p, a basic helix-loop-helix/leucine zipper protein that functions in mitochondrial-induced changes in gene expression, contains independent activation domains. 924 40

We have adapted a LacZ promoter trap screen developed by Burns et al. (1994) to search for genes whose expression is dependent on Rtg2p, a protein with an N-terminal hsp70/actin/sugar kinase ATP binding domain. Rtg2p acts upstream of the basic helix-loop-helix/leucine zipper transcription factors, Rtg1p and Rtg3p. All three proteins are known to be required for the expression of the CIT2 gene, which encodes a peroxisomal isoform of citrate synthase whose expression is also dependent on the functional state of mitochondria. Using this screen, we have identified a previously uncharacterized gene, YEL071w, predicted to encode a protein of 496 amino acids that shares 80% homology and 60% sequence identity with actin interacting protein 2, encoded by the AIP2 gene; both proteins also share sequence similarity to aD-lactate dehydrogenase encoded by the DLD1 gene. Expression of YEL071w is dependent on the functional state of mitochondria and on all three of the Rtg proteins, whereas AIP2 expression is independent of the Rtg proteins and the functional state of mitochondria. Like CIT2, the 5' flanking region of YEL071w contains two R box binding sites for the Rtg1p/Rtg3p heterodimeric transcription complex. Both R boxes are necessary for full YEL071w expression. We show that YEL071w and AIP2 encode proteins withD-lactate dehydrogenase activity, the former located in the cytoplasm and the latter in the mitochondrial matrix. Our data thus provide gene assignments for two previously unrecognized D-lactate dehydrogenase activities in yeast.
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PMID:Signalling between mitochondria and the nucleus regulates the expression of a new D-lactate dehydrogenase activity in yeast. 1050 19

The basic helix-loop-helix (bHLH) proteins comprise a eukaryotic transcription factor family involved in multiple biological processes. They have the ability to form multiple dimer combinations and most of them also bind a 6 bp site (E-box) with limited specificity. These properties make them ideal for combinatorial regulation of gene expression. The Saccharomyces cerevisiae CIT2 gene, which encodes citrate synthase, was previously known to be induced by the bHLH proteins Rtg1p and Rtg3p in response to mitochondrial damage. Rtg1p-Rtg3p dimers bind two R-boxes (modified E-boxes) in the CIT2 promoter. The current study tested the ability of all nine S. cerevisiae bHLH proteins to regulate the CIT2 gene. The results showed that expression of CIT2-lacZ reporter was induced in a rho(0) strain by the presence of inositol via the Ino2p and Ino4p bHLH proteins, which are known regulators of phospholipid synthesis. Promoter mutations revealed that inositol induction required a distal E-box in the CIT2 promoter. Interestingly, deleting the INO2, INO4 genes or the cognate E-box revealed phosphate induction of CIT2 expression. This layer of expression required the two R-boxes and the Pho4p bHLH protein, which is known to be required for phosphate-specific regulation. Lastly, the data show that the Hms1p and Sgc1p bHLH proteins also play important roles in repression of CIT2-lacZ expression. Collectively, these results support the model that yeast bHLH proteins coordinate different biological pathways.
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PMID:Multiple bHLH proteins regulate CIT2 expression in Saccharomyces cerevisiae. 2016 31