GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation

Abstract

The amino acid Glutamine is converted into Glutamate by a deamidation reaction catalyzed by the enzyme Glutaminase (GLS). Two isoforms of this enzyme have been described, and the GLS2 isoform is regulated by the tumor suppressor gene p53. Here, we show that the p53 family member TAp73 also drives the expression of GLS2. Specifically, we demonstrate that TAp73 regulates GLS2 during retinoic acid-induced terminal neuronal differentiation of neuroblastoma cells, and overexpression or inhibition of GLS2 modulates neuronal differentiation and intracellular levels of ATP. Moreover, inhibition of GLS activity, by removing Glutamine from the growth medium, impairs in vitro differentiation of cortical neurons. Finally, expression of GLS2 increases during mouse cerebellar development. Although, p73 is dispensable for the in vivo expression of GLS2, TAp73 loss affects GABA and Glutamate levels in cortical neurons. Together, these findings suggest a role for GLS2 acting, at least in part, downstream of p73 in neuronal differentiation and highlight a possible role of p73 in regulating neurotransmitter synthesis

Glutaminase 1 Is Essential for the Differentiation, Proliferation, and Survival of Human Neural Progenitor Cells

“…*P < 0.05, **P < 0.01, ***P < 0.001 compared with the control siRNA group, n = 3. Color images available online at www.liebertpub.com/scd GLS2 on neuronal differentiation [29]. Since GLS1 expression is at a much higher level in mammalian CNS compared with GLS2, tight regulation of GLS1 is of critical importance to brain homeostasis.…”

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

“…Upregulates glutamine metabolism enzymes and transporters 6,31,48,145,177 KRAS mutations Drives dependence on glutamine metabolism, suppresses GLUD, and drives NADPH via malic enzyme 1 (ME1) 34,108,119,157,158 HIF1α or HIF2α stabilization Drives reductive carboxylation of glutamine to citrate for lipid production [89][90][91] HER2 upregulation Activates glutamine metabolism through MYC and NF-κB 156,220 p53, p63, or p73 activity Activates GLS2 expression 55,56,62,63 JAK2-V617F mutation Activates GLS and increases glutamine metabolism 221 mTOR upregulation Promotes glutamine metabolism via induction of MYC 155 and GLUD 69,73 or aminotransferases 117 NRF2 activation Promotes production of glutathione from glutamine 222 TGFβ-WNT upregulation Promotes SNAIL and DLX2 activation, which upregulate GLS and activates epithelial-mesenchymal transition 183 PKC zeta loss Stimulates glutamine metabolism through serine synthesis 223 …”

“…However, GLS2 seems to support the growth and promote radiation resistance in some cancer types 61 . Indeed, GLS2 is induced by the tumor suppressor p53 and related proteins p63 and p73 55,56,62,63 , suggesting perhaps that it functions in resistance to radiation, or is important in cancers that still possess wild-type p53. Additionally, GLS2 is a critical downstream target of the N-MYC oncogene in neuroblastoma 64,65 .…”

Vascular ageing and endothelial cell senescence: Molecular mechanisms of physiology and diseases

“…Metabolic regulation by p53 family appears a key function for their cancer-related but also ageing-related phenotype. All the three members promote mitochondrial respiration thought regulation of different metabolic enzymes, including the glutaminase 2 (Gls2) (Adamovich et al, 2014;Amelio et al, 2014b;Bellomaria et al, 2010Bellomaria et al, , 2012Giacobbe et al, 2013;He et al, 2013;Hu et al, 2010;Sharif et al, 2015;Simon et al, 2014;Velletri et al, 2013;Viticchie et al, 2015). Gls2 regulates glutamine utilization, supplying anaplerotic flux of substrates resulting in promotion of mitochondrial activity and ATP synthesis (Amelio et al, 2014a;Maniam et al, 2015).…”