RRC ID 36127
著者 Slaninova V, Krafcikova M, Perez-Gomez R, Steffal P, Trantirek L, Bray SJ, Krejci A.
タイトル Notch stimulates growth by direct regulation of genes involved in the control of glycolysis and the tricarboxylic acid cycle.
ジャーナル Open Biol
Abstract Glycolytic shift is a characteristic feature of rapidly proliferating cells, such as cells during development and during immune response or cancer cells, as well as of stem cells. It results in increased glycolysis uncoupled from mitochondrial respiration, also known as the Warburg effect. Notch signalling is active in contexts where cells undergo glycolytic shift. We decided to test whether metabolic genes are direct transcriptional targets of Notch signalling and whether upregulation of metabolic genes can help Notch to induce tissue growth under physiological conditions and in conditions of Notch-induced hyperplasia. We show that genes mediating cellular metabolic changes towards the Warburg effect are direct transcriptional targets of Notch signalling. They include genes encoding proteins involved in glucose uptake, glycolysis, lactate to pyruvate conversion and repression of the tricarboxylic acid cycle. The direct transcriptional upregulation of metabolic genes is PI3K/Akt independent and occurs not only in cells with overactivated Notch but also in cells with endogenous levels of Notch signalling and in vivo. Even a short pulse of Notch activity is able to elicit long-lasting metabolic changes resembling the Warburg effect. Loss of Notch signalling in Drosophila wing discs as well as in human microvascular cells leads to downregulation of glycolytic genes. Notch-driven tissue overgrowth can be rescued by downregulation of genes for glucose metabolism. Notch activity is able to support growth of wing during nutrient-deprivation conditions, independent of the growth of the rest of the body. Notch is active in situations that involve metabolic reprogramming, and the direct regulation of metabolic genes may be a common mechanism that helps Notch to exert its effects in target tissues.
巻・号 6(2)
ページ 150155
公開日 2016-2-1
DOI 10.1098/rsob.150155
PII rsob.150155
PMID 26887408
PMC PMC4772804
MeSH Animals Binding Sites Cell Line Citric Acid Cycle / genetics* Drosophila Proteins / genetics Drosophila Proteins / metabolism Energy Metabolism / genetics Gene Expression Gene Expression Regulation* Genes, Reporter Glycolysis / genetics* Humans Models, Biological Promoter Regions, Genetic Protein Binding Receptors, Notch / genetics Receptors, Notch / metabolism* Regulatory Sequences, Nucleic Acid Repressor Proteins / genetics Repressor Proteins / metabolism Transcriptional Activation
IF 4.931
引用数 25
WOS 分野 BIOCHEMISTRY & MOLECULAR BIOLOGY
リソース情報
ショウジョウバエ DGRC#105136