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Gene Section Review Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL INIST-CNRS Gene Section Review GLS2 (Glutaminase 2) José A Campos-Sandoval, Mercedes Martín-Rufián, Javier Márquez Department of Molecular Biology and Biochemistry, Faculty of Sciences, Campus de Teatinos, University of Málaga, 29071 Málaga, Spain, and Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Málaga, Spain; [email protected], [email protected], [email protected] Published in Atlas Database: April 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/GLS2ID46328ch12q13.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70607/04-2019-GLS2ID46328ch12q13.pdf DOI: 10.4267/2042/70607 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology GLS, regulated by oncogenes and associated to Abstract tumorigenesis. However, recent findings indicate Mammalian glutaminases are encoded by two that GLS2 is upregulated in some types of cancer paralogous genes, Gls and Gls2, presumably derived (NMYC-amplified neuroblastoma, cervical, colon by gene duplication of a common ancestor. Each and lung cancers) and this upregulation gene codes for two different isoforms. The two paradoxically correlates with poor clinical outcomes. transcripts of Gls2, named GAB and LGA, arise Keywords through a surrogate promoter usage mechanism. In Glutaminase; Neuroblastoma; Cervical cancer; certain types of malignancies, such as glioblastoma Colon cancer; Lung cancer and liver cancers, expression of GLS2 gene is repressed by promoter hypermethylation, which could contribute to the malignant process. The Identity finding that ectopic expression of GLS2 could Other names: GA, PAG, GAB, LGA, hLGA inhibit proliferation of these tumors led to the hypothesis that this isoenzyme, a transcriptional HGNC (Hugo): GLS2 target of TP53, might play a role as tumor Location: 12q13.3 suppressor, in opposition to Figure 1. Genomic structure of human glutaminase GLS2 gene and alternative transcripts GAB and LGA. Introns are depicted as solid light blue lines and exons as numbered dark blue boxes. Dashed red or dotted black lines indicate the exons involved in the generation of GAB and LGA transcripts, respectively (Campos-Sandoval et al., 2015). DNA/RNA Atlas Genet Cytogenet Oncol Haematol. 2019; 23(11) 326 GLS2 (Glutaminase 2) Campos-Sandoval JA et al. Description differentiation and in cancer cells exposed to oxidative stress (Giacobbe et al., 2013), respectively. Human GLS2 gene is located on chromosome 12 The GLS2 downregulation observed in liver and (Aledo et al., 2000). It is composed of 18 exons and colon cancer cell lines and in hepatocellular spans approximately 18 kb (Pérez-Gómez et al., carcinoma has been attributed to its promoter 2003). The gene resides on the minus strand. It starts hypermethylation, a mechanism that has been at 56470944 and ends at 56488414 from pter (NCBI, proposed as a marker to identify novel tumor Gene ID 27165). suppressor genes. Chemical demethylation treatment Transcription increased the GLS2 mRNA levels in these cells Two GLS2 transcripts coding for functional proteins (Zhang et al., 2013; Liu et al., 2014). This have been described: a long canonical one mechanism is also responsible for the GLS2 containing all 18 exons (GAB), cloned from a human silencing detected in highly malignant breast cancer cell line (Gómez-Fabre et al., 2000) glioblastomas, and occurs regardless of their TP53 and a short variant (LGA), first characterized in rat status (Szeliga et al., 2016). Other factors that liver (Smith and Watford, 1990; Chung-Bok et al., regulate GLS2 expression are the MYCN 1997) and lacking the first exon (Martèn-Rufián et oncoprotein (v-myc avian myelocytomatosis viral al., 2012). LGA transcript arises by a combination of oncogene neuroblastoma derived homolog, encoded two mechanisms of transcriptional regulation: by MYCN gene) and the NR5A2 (nuclear receptor alternative transcription initiation and alternative subfamily 5 group A member 2), also known as promoter. Its transcription start site is located at 3- LRH-1 (liver receptor homolog 1). MYCN, an end of the first intron of GLS2 gene. Other non- essential MYC family member, directly activates coding transcripts, containing premature stop GLS2 transcription in MYCN-amplified codons, have been isolated (Martèn-Rufián et al., neuroblastoma cells. Depletion of MYCN 2012). expression by short hairpin RNA caused a The molecular basis for GLS2 regulation is now pronounced decrease in GLS2 (but not GLS) levels starting to be uncovered. GLS2 has been identified in these cells. Conversely, inhibition of TP53 had no as a transcriptional target of tumor suppressor TP53 effect on GLS2 induction (Xiao et al., 2015). In that mediates its new revealed functions in tumor hepatoma cells, GLS2 is subjected to direct metabolism and antioxidant defense, under both transcriptional regulation by NR5A2. Silencing of non-stressed and stressed conditions. This tumor NR5A2 mediated by small interfering RNA reduced suppressor directly associates with response GLS2 transcript and protein levels (Xu et al., 2016). elements in the GLS2 promoter (Hu et al., 2010; Long non-coding RNA (lncRNA) and microRNAs Suzuki et al., 2010). Cells with heightened GLS2 (miRNAs) are also implicated in GLS2 regulation. levels showed increased production of glutamate and The lncRNA urothelial carcinoma-associated 1 ( alpha-ketoglutarate, which resulted in enhanced UCA1) regulates GLS2 expression levels through oxydative phosphorylation, higher GSH/GSSG interfering with MIR16-1, which binds to the 3'-UTR ratios and decreased reactive oxygen species (ROS) (untranslated region) of GLS2 mRNA (Li et al., levels, which provided protection against ROS 2016). induced apoptosis (Hu et al., 2010; Suzuki et al., 2010). Two other transcription factors belonging to Pseudogene the TP53 family, TP73 and TP63, also drive the At least one pseudogene has been reported for GLS2 expression of GLS2 during neuronal differentiation (GenBank: AF110329.1). of neuroblastoma cells after induction with retinoic acid (Velletri et al., 2013) and during epidermal Figure 2. Schematic diagram of GLS2 isoforms showing the localization of predicted domains and motifs by sequence analysis (Márquez et al., 2016). Protein Atlas Genet Cytogenet Oncol Haematol. 2019; 23(11) 327 GLS2 (Glutaminase 2) Campos-Sandoval JA et al. Description Studies on processing and molecular structure of native GLS2 protein are lacking. An apparent Purification: the first attempts to purify liver-type subunit molecular mass of 57-58 kDa for the rat liver glutaminase from rat liver only yielded partial isoform was determined by denaturing gel purifications: 15-fold (Huang and Knox, 1976) and electrophoresis of purified protein (Heini et al., 60-fold (Patel and McGivan, 1984). Unlike kidney- 1987; Smith and Watford, 1988). Sequencing by type glutaminase (KGA), the liver isoenzyme does Edman degradation of the mature form of human not polymerize in the presence of phosphate-borate GAB expressed in baculovirus system showed buffer (Huang and Knox, 1976). This different cleavage between amino acids 38-39 and 39-40 of behaviour, together with its greater instability in the deduced protein sequence. These cleavages are tissue homogenates and diluted preparations, made consistent with known substrate sites for the this isoenzyme more difficult to purify than KGA. In mitochondrial processing peptidase (MPP), having fact, its purification to near homogeneity was not an Arg residue at position -2 or -3. Nevertheless, achieved until almost two decades later than KGA processing in baculovirus system may somehow purification. Heini et al. (1987) purified rat LGA differ from the native processing in mammals 400-fold, while Smith and Watford (1988) reported (Campos-Sandoval et al., 2007). The molecular mass a 600-fold purification, with specific activities of 30- (Mr) of native GLS2 has not been determined 50 μmol/min per mg protein. Human GAB accurately. Smith and Watford (1988) reported an isoenzyme has been expressed as a recombinant Mr of ≥ 300000 from HPLC gel filtration but protein in baculovirus system and purified by obtained a value of 162000 by sucrose gradient affinity chromatography with a specific activity of centrifugation, regardless of phosphate 18 μmol/min per mg protein (Campos-Sandoval et concentration (5 or 100 mM). al., 2007). Kinetic properties: the distinct kinetic behavior of Structure: human GAB transcript (ORF: 1809 nt) mammalian kydney-type and liver-type isoenzymes codes a 602-residues protein, with a predicted was first noted by Krebs (1935). In contrast with molecular mass of 66.3 kDa. Human LGA transcript kydney-type isoenzyme, the rat liver-type (ORF: 1698 nt) codes a 565-residues protein, with a glutaminase showed a lower dependence on the predicted molecular mass of 62.5 kDa. The precursor activator inorganic phosphate (Pi), lower affinity for of human LGA isoform lacks the first 61 residues of the substrate glutamine, lack of inhibition by GAB precursor (coded by exon 1), but it displays an glutamate (up to 50 mM) and a requirement for additional extension of 24 novel residues at the N- ammonia as an obligatory activator (Verhoeven et terminus coded by an alternative first exon. This al., 1983; Patel and McGivan, 1984; Smith and extension and the first six amino acids coded by exon Watford, 1988). The
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