title: Notch stimulates growth by direct regulation of genes involved in the control of glycolysis and the tricarboxylic acid cycle.
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.
authors.affiliation: Faculty of Science, University of South Bohemia, Branisovska 31, 37005 Ceske Budejovice, Czech Republic Institute of Entomology, Biology Centre, Czech Academy of Sciences, 37005 Ceske Budejovice, Czech Republic.
authors.forename: Vera
authors.initials: V
authors.lastname: Slaninova
authors.affiliation: Central European Institute of Technology, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Krafcikova
authors.affiliation: Faculty of Science, University of South Bohemia, Branisovska 31, 37005 Ceske Budejovice, Czech Republic.
authors.forename: Raquel
authors.initials: R
authors.lastname: Perez-Gomez
authors.affiliation: Faculty of Science, University of South Bohemia, Branisovska 31, 37005 Ceske Budejovice, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Steffal
authors.affiliation: Central European Institute of Technology, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic.
authors.forename: Lukas
authors.initials: L
authors.lastname: Trantirek
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Bray
authors.affiliation: Faculty of Science, University of South Bohemia, Branisovska 31, 37005 Ceske Budejovice, Czech Republic Institute of Entomology, Biology Centre, Czech Academy of Sciences, 37005 Ceske Budejovice, Czech Republic akrejci@prf.jcu.cz.
authors.forename: Alena
authors.identifier: http://orcid.org/0000-0001-7589-4035
authors.initials: A
authors.lastname: Krejci
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002952:Citric Acid Cycle / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics; D015870:Gene Expression; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006019:Glycolysis / Q000235:genetics*; D006801:Humans; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D029721:Drosophila Proteins; D051880:Receptors, Notch; D012097:Repressor Proteins; C088731:Su(H) protein, Drosophila
keywords: Notch targets; Warburg effect; glycolytic shift; metabolism; tissue growth