Loss of function mutation of the Slc38a3 glutamine transporter reveals its critical role for amino acid metabolism in the liver, brain, and kidney

Chan, Kessara; Busque, Stephanie M.; Sailer, Manuela; Stoeger, Claudia; Bröer, Stefan; Daniel, Hannelore; Rubio‐Aliaga, Isabel; Wagner, Carsten A.

doi:10.1007/s00424-015-1742-0

Cited by 44 publications

(61 citation statements)

References 56 publications

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“…Among the known members of the SLC38 gene family, the consequences of gene deletion are known thus far only for Slc38a3 [84]. The knockout mice show growth retardation, hypoglycemia, and impaired mTORC1 signaling; the mice die within 20 days of birth.…”

Section: Slc38a1 Slc38a2 Slc38a3 Slc38a5 Slc38a7 and Slc38a8mentioning

confidence: 99%

Glutamine transporters in mammalian cells and their functions in physiology and cancer

Bhutia

Ganapathy

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

232

226

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The SLC (solute carrier)-type transporters (∼400 in number) in mammalian cells consist of 52 distinct gene families, grouped solely based on the amino acid sequence (primary structure) of the transporter proteins and not on their transport function. Among them are the transporters for amino acids. Fourteen of them, capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine. Some of the glutamine transporters are obligatory exchangers whereas some function as active transporters in one direction. While most glutamine transporters mediate the influx of the amino acid into cells, some actually mediate the efflux of the amino acid out of the cells. Glutamine transporters play important roles in a variety of tissues, including the liver, brain, kidney, and placenta, as clearly evident from the biological and biochemical phenotypes resulting from the deletion of specific glutamine transporters in mice. Owing to the obligatory role of glutamine in growth and proliferation of tumor cells, there is increasing attention on glutamine transporters in cancer biology as potential drug targets for cancer treatment. Selective blockers of certain glutamine transporters might be effective in preventing the entry of glutamine and other important amino acids into tumor cells, thus essentially starving these cells to death. This could represent the beginning of a new era in the discovery of novel anticancer drugs with a previously unexplored mode of action.

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Section: Slc38a1 Slc38a2 Slc38a3 Slc38a5 Slc38a7 and Slc38a8mentioning

confidence: 99%

Glutamine transporters in mammalian cells and their functions in physiology and cancer

Bhutia

Ganapathy

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

232

226

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“…The 14 human GLUT proteins, encoded by the SLC2 gene, have various substrate specificities and are involved in the transport of several hexoses in addition to myoinositol . GLUT proteins in the digestive system serve as important mediators in maintaining normal functions, including the absorption of nutrients and ions, excretion of bile acids, and metabolism of toxins . Dysregulation of the SLC2 gene is likely to be associated with carcinogenesis, tumor progression, metastasis, and chemoresistance.…”

Section: Discussionmentioning

confidence: 99%

“…39 GLUT proteins in the digestive system serve as important mediators in maintaining normal functions, including the absorption of nutrients and ions, excretion of bile acids, and metabolism of toxins. [40][41][42] Dysregulation of the SLC2 gene is likely to be associated with carcinogenesis, tumor progression, metastasis, and chemoresistance.…”

Section: Discussionmentioning

confidence: 99%

Three novel genetic variants in NRF2 signaling pathway genes are associated with pancreatic cancer risk

et al. 2019

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Pancreatic cancer (PanC) is one of the most lethal solid malignancies, and metastatic PanC is often present at the time of diagnosis. Although several high‐ and low‐penetrance genes have been implicated in PanC, their roles in carcinogenesis remain only partially elucidated. Because the nuclear factor erythroid2‐related factor2 (NRF2) signaling pathway is involved in human cancers, we hypothesize that genetic variants in NRF2 pathway genes are associated with PanC risk. To test this hypothesis, we assessed associations between 31 583 common single nucleotide polymorphisms (SNP) in 164 NRF2‐related genes and PanC risk using three published genome‐wide association study (GWAS) datasets, which included 8474 cases and 6944 controls of European descent. We also carried out expression quantitative trait loci (eQTL) analysis to assess the genotype‐phenotype correlation of the identified significant SNP using publicly available data in the 1000 Genomes Project. We found that three novel SNP (ie, rs3124761, rs17458086 and rs1630747) were significantly associated with PanC risk ( P = 5.17 × 10 −7 , 5.61 × 10 −4 and 5.52 × 10 −4 , respectively). Combined analysis using the number of unfavorable genotypes (NUG) of these three SNP suggested that carriers of two to three NUG had an increased risk of PanC ( P < 0.0001), compared with those carrying zero to one NUG. Furthermore, eQTL analysis showed that both rs3124761 T and rs17458086 C alleles were associated with increased mRNA expression levels of SLC2A6 and SLC2A13 , respectively ( P < 0.05). In conclusion, genetic variants in NRF2 pathway genes could play a role in susceptibility to PanC, and further functional exploration of the underlying molecular mechanisms is warranted.

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“…Moreover, it was demonstrated that silencing of system N transporters causes the retention of Gln in astrocytes and that ammonia-derived Gln release from astrocytes is mediated by impairing of SN1-mediated Gln efflux [13,25]. SN1 is abundant in neocortex, cerebellum and olfactory bulb, therefore the functional ablation of this transporter with N-ethyl-N-nitrosourea (ENU)-induced mutagenesis in vivo leads to ataxia in mice [26]. This, albeit indirectly, confirms the important role of SN1 in sustaining proper neurotransmission.…”

Section: Introductionmentioning

confidence: 99%

SN1 Transporter Regulation by Sp1 in Ammonia-Treated Mouse Cortical Astrocytes: Role of Sp1 Phosphorylation Status

Dąbrowska¹,

Zielińska²

2018

Preprint

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The involvement of astrocytic SN1 (SNAT3) transporter in ammonia-induced L-glutamine retention was recently documented in mouse cultured astrocytes. Here we investigated the involvement of specificity protein 1 (Sp1) transcription factor in SN1 regulation in ammonium chloride (“ammonia”)-treated astrocytes. Sp1 expression and its cellular localization were determined using real-time qPCR, Western blot and confocal microscopy, respectively. Sp1 binding to Snat3 promoter was analyzed by chromatin immunoprecipitation. Ammonia-induced Sp1 regulatory role in SN1-mediated [3H]glutamine transport was verified using siRNA and mithramycin A. The involvement of protein kinase C (PKC) isoforms in Sp1 level/phosphorylation status was verified using siRNA technology. Sp1 translocation to the nuclei and its enhanced binding to Snat3 promoter, along with Sp1 dependence of system N-mediated [3H]glutamine transport were observed in astrocytes upon ammonia exposure. Ammonia decreased the level of phosphorylated Sp1, and the effect was reinforced by long-term incubation with PKC modulator, phorbol 12-myristate 13-acetate, a treatment likely to dephosphorylate Sp1. Furthermore,  silencing of PKCδ isoform abolished the increase of Sp1 level by ammonia. Collectively, the results demonstrate the regulatory role of Sp1 in regulation of SN1 expression and activity in ammonia-treated astrocytes and implicate altered Sp1 phosphorylation status in this capacity.

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Loss of function mutation of the Slc38a3 glutamine transporter reveals its critical role for amino acid metabolism in the liver, brain, and kidney

Cited by 44 publications

References 56 publications

Glutamine transporters in mammalian cells and their functions in physiology and cancer

Glutamine transporters in mammalian cells and their functions in physiology and cancer

Three novel genetic variants in NRF2 signaling pathway genes are associated with pancreatic cancer risk

SN1 Transporter Regulation by Sp1 in Ammonia-Treated Mouse Cortical Astrocytes: Role of Sp1 Phosphorylation Status

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