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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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Potential Atf4 binding sites are found in the promoters of glycolytic genes and Ldh. Schematic representations of the location of putative Atf4 binding sites are shown. Arrows indicate transcription start sites as annotated in FlyBase, and arrowheads indicate consensus Atf4 binding CREs (TGACGT; gray) and the Atf4 binding motif identified in mouse embryonic fibroblasts (Han et al. 2013) (TT(G/T)CATCA(G/T); black). We examined 2 kb upstream and 0.5 kb downstream of all transcription start sites. Genes whose expression was up-regulated by twofold or greater by DTT are indicated in bold (see Figure 1); others were not changed during ER stress. Atf4, activating transcription factor 4; DTT, dithiothreitol; ER, endoplasmic reticulum; Ldh, Lactate dehydrogenase.
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fig4: Potential Atf4 binding sites are found in the promoters of glycolytic genes and Ldh. Schematic representations of the location of putative Atf4 binding sites are shown. Arrows indicate transcription start sites as annotated in FlyBase, and arrowheads indicate consensus Atf4 binding CREs (TGACGT; gray) and the Atf4 binding motif identified in mouse embryonic fibroblasts (Han et al. 2013) (TT(G/T)CATCA(G/T); black). We examined 2 kb upstream and 0.5 kb downstream of all transcription start sites. Genes whose expression was up-regulated by twofold or greater by DTT are indicated in bold (see Figure 1); others were not changed during ER stress. Atf4, activating transcription factor 4; DTT, dithiothreitol; ER, endoplasmic reticulum; Ldh, Lactate dehydrogenase.

Mentions: Atf4 is a member of the bZIP family of transcription factors, which regulate target genes through the CRE (TGACGT) (Lin and Green 1988). A recent chromatin immunoprecipitation-RNA sequencing study also identified the TT(G/T)CATCA(G/T) motif as an Atf4 binding site in mouse embryonic fibroblasts (Han et al. 2013). We examined the promoter regions of glycolytic genes in D. melanogaster (2 kb upstream and 0.5 kb downstream of the annotated transcription start sites) and found that six of the seven glycolytic genes up-regulated by ER stress contained at least one of these Atf4 binding sites. Conversely, only one of the four glycolytic genes not significantly up-regulated by ER stress contained an Atf4 binding site (Figure 4).


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)

Potential Atf4 binding sites are found in the promoters of glycolytic genes and Ldh. Schematic representations of the location of putative Atf4 binding sites are shown. Arrows indicate transcription start sites as annotated in FlyBase, and arrowheads indicate consensus Atf4 binding CREs (TGACGT; gray) and the Atf4 binding motif identified in mouse embryonic fibroblasts (Han et al. 2013) (TT(G/T)CATCA(G/T); black). We examined 2 kb upstream and 0.5 kb downstream of all transcription start sites. Genes whose expression was up-regulated by twofold or greater by DTT are indicated in bold (see Figure 1); others were not changed during ER stress. Atf4, activating transcription factor 4; DTT, dithiothreitol; ER, endoplasmic reticulum; Ldh, Lactate dehydrogenase.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: Potential Atf4 binding sites are found in the promoters of glycolytic genes and Ldh. Schematic representations of the location of putative Atf4 binding sites are shown. Arrows indicate transcription start sites as annotated in FlyBase, and arrowheads indicate consensus Atf4 binding CREs (TGACGT; gray) and the Atf4 binding motif identified in mouse embryonic fibroblasts (Han et al. 2013) (TT(G/T)CATCA(G/T); black). We examined 2 kb upstream and 0.5 kb downstream of all transcription start sites. Genes whose expression was up-regulated by twofold or greater by DTT are indicated in bold (see Figure 1); others were not changed during ER stress. Atf4, activating transcription factor 4; DTT, dithiothreitol; ER, endoplasmic reticulum; Ldh, Lactate dehydrogenase.
Mentions: Atf4 is a member of the bZIP family of transcription factors, which regulate target genes through the CRE (TGACGT) (Lin and Green 1988). A recent chromatin immunoprecipitation-RNA sequencing study also identified the TT(G/T)CATCA(G/T) motif as an Atf4 binding site in mouse embryonic fibroblasts (Han et al. 2013). We examined the promoter regions of glycolytic genes in D. melanogaster (2 kb upstream and 0.5 kb downstream of the annotated transcription start sites) and found that six of the seven glycolytic genes up-regulated by ER stress contained at least one of these Atf4 binding sites. Conversely, only one of the four glycolytic genes not significantly up-regulated by ER stress contained an Atf4 binding site (Figure 4).

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