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.

Revisiting the role of metabolism during development

“…It has been shown that Lin28a downregulation constitutes a developmental cue that controls metabolic rewiring in embryos that are undergoing placental development (Miyazawa et al, 2017;Shinoda et al, 2013). Metabolic transitions that are regulated by intrinsic developmental programs have also been identified in other developmental and/or organismal contexts (Agathocleous et al, 2012;Bulusu et al, 2017;Homem et al, 2014;Oginuma et al, 2017;Slaninova et al, 2016;Tennessen et al, 2011). It therefore appears that the timing of metabolic rewiring is coordinated with developmental progression via the integration of both extrinsic and intrinsic cues.…”

Complement-Mediated Regulation of Metabolism and Basic Cellular Processes

“…The possibility for a ‘CD46-like’ role assigned to Notch in the mouse system is further supported by the fact that Notch is critically involved in regulating the same metabolic pathways as CD46 does in humans (Ciofani and Zuniga-Pflucker, 2005; Landor et al, 2011; Maekawa et al, 2015; Xu et al, 2015). Moreover, a recent study has identified Glut1 , and other key genes involved in the regulation of glycolysis and the tricarboxylic acid cycle, as direct transcriptional targets of Notch1 in mice (Slaninova et al, 2016). It is not clear why rodents ‘avoided’ CD46 expression during evolution.…”

A genetic toolkit for the analysis of metabolic changes in Drosophila provides new insights into metabolic responses to stress and malignant transformation

“…Constitutive activation of the Notch pathway in wing imaginal discs produce deregulated growth and hyperplastic tumors (34), which depend on the induction of glycolysis-related genes such as LDH, Hexokinase A, and Glut1. Using Laconic, we analyzed intracellular lactate levels in these developing tumors, and found no significant differences in comparison to normal tissues (Fig 6A and B).…”