title: 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.
authors.affiliation: Medical Research Council; Toxicology Unit; Leicester University; Leicester, UK; Institute of Health Sciences; Shanghai Institutes for Biological Sciences; Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine; Shanghai, China.
authors.forename: Tania
authors.initials: T
authors.lastname: Velletri
authors.forename: Francesco
authors.initials: F
authors.lastname: Romeo
authors.forename: Paola
authors.initials: P
authors.lastname: Tucci
authors.forename: Angelo
authors.initials: A
authors.lastname: Peschiaroli
authors.forename: Margherita
authors.initials: M
authors.lastname: Annicchiarico-Petruzzelli
authors.forename: Maria Victoria
authors.initials: MV
authors.lastname: Niklison-Chirou
authors.forename: Ivano
authors.initials: I
authors.lastname: Amelio
authors.forename: Richard A
authors.initials: RA
authors.lastname: Knight
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Agostini
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002531:Cerebellum / Q000254:growth & development / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005972:Glutaminase / Q000235:genetics* / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014212:Tretinoin / Q000494:pharmacology; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D014212:Tretinoin; C586504:GLS2 protein, human; D005972:Glutaminase
keywords: GLS2; apoptosis; metabolism; neuronal differentiation; neurotransmitter; p53 family; p73