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Drosophila melanogaster activating transcription factor 4 regulates glycolysis during endoplasmic reticulum stress.

Lee JE, Oney M, Frizzell K, Phadnis N, Hollien J - G3 (Bethesda) (2015)

Bottom Line: The unfolded protein response transcription factor Atf4 was necessary for the up-regulation of glycolytic enzymes and Lactate dehydrogenase (Ldh).Finally, flies up-regulated Ldh and produced more lactate when subjected to ER stress.Together, these results suggest that Atf4 mediates a shift from a metabolism based on oxidative phosphorylation to one more heavily reliant on glycolysis, reminiscent of aerobic glycolysis or the Warburg effect observed in cancer and other proliferative cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of Utah, Salt Lake City, Utah 84112.

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Related in: MedlinePlus

Microarray analysis reveals a coordinated change in the expression of metabolic genes in S2 cells treated with dithiothreitol (DTT). (A) We analyzed the expression of genes in glycolysis, the tricarboxylic acid (TCA) cycle, and the respiratory chain complex using previously published microarray data (Hollien and Weissman 2006). Briefly, S2 cells were incubated with and without DTT (2 mM, 7 hr), and relative RNA levels were measured by Affymetrix microarrays. In parallel, S2 cells were depleted of the indicated factors by RNA interference, then incubated with and without DTT (2 mM, 7.4 hr). Relative RNA levels were then measured by spotted microarray. Further details and complete data are available at the Gene Expression Omnibus, accession GPL3781 (http://www.ncbi.nlm.nih.gov/geo/). (B) Schematic diagram of glucose metabolism with expression data from (A). Red indicates mRNA levels were up-regulated at least 2-fold by DTT, blue indicates down-regulation by at least 1.5-fold, and black indicates changes between these thresholds.
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fig1: Microarray analysis reveals a coordinated change in the expression of metabolic genes in S2 cells treated with dithiothreitol (DTT). (A) We analyzed the expression of genes in glycolysis, the tricarboxylic acid (TCA) cycle, and the respiratory chain complex using previously published microarray data (Hollien and Weissman 2006). Briefly, S2 cells were incubated with and without DTT (2 mM, 7 hr), and relative RNA levels were measured by Affymetrix microarrays. In parallel, S2 cells were depleted of the indicated factors by RNA interference, then incubated with and without DTT (2 mM, 7.4 hr). Relative RNA levels were then measured by spotted microarray. Further details and complete data are available at the Gene Expression Omnibus, accession GPL3781 (http://www.ncbi.nlm.nih.gov/geo/). (B) Schematic diagram of glucose metabolism with expression data from (A). Red indicates mRNA levels were up-regulated at least 2-fold by DTT, blue indicates down-regulation by at least 1.5-fold, and black indicates changes between these thresholds.

Mentions: To explore the regulation of metabolism during ER stress, we examined gene expression patterns from our previously published microarray studies of D. melanogaster S2 cells (Hollien and Weissman 2006). We found that the mRNA levels of most enzymes involved in central carbon metabolism changed when cells were treated with DTT (2 mM), a reducing agent that induces ER stress by disrupting disulfide bond formation within the ER. In response to DTT, genes encoding glycolytic enzymes were up-regulated whereas genes encoding TCA cycle enzymes and the respiratory chain complexes were down-regulated (Figure 1 and Supporting Information, Table S1). In addition, expression of Lactate dehydrogenase (Ldh, also known as ImpL3 and CG10160), which codes for the enzyme that converts pyruvate to lactate, was dramatically increased. These changes in metabolic gene expression suggest a shift in glucose metabolism from OXPHOS to glycolysis.


Drosophila melanogaster activating transcription factor 4 regulates glycolysis during endoplasmic reticulum stress.

Lee JE, Oney M, Frizzell K, Phadnis N, Hollien J - G3 (Bethesda) (2015)

Microarray analysis reveals a coordinated change in the expression of metabolic genes in S2 cells treated with dithiothreitol (DTT). (A) We analyzed the expression of genes in glycolysis, the tricarboxylic acid (TCA) cycle, and the respiratory chain complex using previously published microarray data (Hollien and Weissman 2006). Briefly, S2 cells were incubated with and without DTT (2 mM, 7 hr), and relative RNA levels were measured by Affymetrix microarrays. In parallel, S2 cells were depleted of the indicated factors by RNA interference, then incubated with and without DTT (2 mM, 7.4 hr). Relative RNA levels were then measured by spotted microarray. Further details and complete data are available at the Gene Expression Omnibus, accession GPL3781 (http://www.ncbi.nlm.nih.gov/geo/). (B) Schematic diagram of glucose metabolism with expression data from (A). Red indicates mRNA levels were up-regulated at least 2-fold by DTT, blue indicates down-regulation by at least 1.5-fold, and black indicates changes between these thresholds.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390581&req=5

fig1: Microarray analysis reveals a coordinated change in the expression of metabolic genes in S2 cells treated with dithiothreitol (DTT). (A) We analyzed the expression of genes in glycolysis, the tricarboxylic acid (TCA) cycle, and the respiratory chain complex using previously published microarray data (Hollien and Weissman 2006). Briefly, S2 cells were incubated with and without DTT (2 mM, 7 hr), and relative RNA levels were measured by Affymetrix microarrays. In parallel, S2 cells were depleted of the indicated factors by RNA interference, then incubated with and without DTT (2 mM, 7.4 hr). Relative RNA levels were then measured by spotted microarray. Further details and complete data are available at the Gene Expression Omnibus, accession GPL3781 (http://www.ncbi.nlm.nih.gov/geo/). (B) Schematic diagram of glucose metabolism with expression data from (A). Red indicates mRNA levels were up-regulated at least 2-fold by DTT, blue indicates down-regulation by at least 1.5-fold, and black indicates changes between these thresholds.
Mentions: To explore the regulation of metabolism during ER stress, we examined gene expression patterns from our previously published microarray studies of D. melanogaster S2 cells (Hollien and Weissman 2006). We found that the mRNA levels of most enzymes involved in central carbon metabolism changed when cells were treated with DTT (2 mM), a reducing agent that induces ER stress by disrupting disulfide bond formation within the ER. In response to DTT, genes encoding glycolytic enzymes were up-regulated whereas genes encoding TCA cycle enzymes and the respiratory chain complexes were down-regulated (Figure 1 and Supporting Information, Table S1). In addition, expression of Lactate dehydrogenase (Ldh, also known as ImpL3 and CG10160), which codes for the enzyme that converts pyruvate to lactate, was dramatically increased. These changes in metabolic gene expression suggest a shift in glucose metabolism from OXPHOS to glycolysis.

Bottom Line: The unfolded protein response transcription factor Atf4 was necessary for the up-regulation of glycolytic enzymes and Lactate dehydrogenase (Ldh).Finally, flies up-regulated Ldh and produced more lactate when subjected to ER stress.Together, these results suggest that Atf4 mediates a shift from a metabolism based on oxidative phosphorylation to one more heavily reliant on glycolysis, reminiscent of aerobic glycolysis or the Warburg effect observed in cancer and other proliferative cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of Utah, Salt Lake City, Utah 84112.

Show MeSH
Related in: MedlinePlus