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ASNS (asparagine synthetase)

Identity

Other namesTS11
HGNC (Hugo) ASNS
LocusID (NCBI) 440
Location 7q21.3
Location_base_pair Starts at 97481429 and ends at 97501854 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Description ASNS is encoded on chromosome 7 and has 14 exons. The promoter begins 173 bases upstream of the start codon, which is on exon 4, with three GC-rich sequences (GC-I, GC-II, and GC-III) followed by two nutrient sensing response elements, NSRE-1 (ATGATGAAA; at nt -70) and NSRE-2 (GTTACA; at nt -49). The stop codon is on exon 14.
Transcription The full length transcript (RefSeq variant 1; NM_133436 on Fig1) is 2348 bp long. Ten alternative splicing isoforms have been reported with most variation occurring primarily in the 5'UTR.
Various forms of cellular stress, including nutrient deprivation, lead to increased ASNS transcription. One component of that mechanism includes translation of the activating transcription factor family of proteins (ATF2, ATF3, ATF4, ATF5, and ATF6), all of which increase ASNS transcription through binding to NSRE-1 and/or NSRE-2. TRB3 is a negative feedback regulator of ATF4-dependent transcription, and C/EBP-beta is a negative regulator of ATF5-dependent transcription. DDIT3/CHOP is also a negative regulator of ASNS transcription.
ASNS has also been reported to be a significant target of transactivation by mutant p53, whereas wild-type p53 inhibits transcriptional activation of the NSREs.
ASNS mRNA has been shown to exhibit a half-life of 9 h and periodic, clock-like up-regulation every around 35 min in cell culture.

Protein

 
  Representation of the ASNS gene, its mRNA splice variants, and its protein isoforms.
Each unique splice variant is identified by an accession number on the left-hand side. Exons are numbered at the top of the image. Lighter green indicates UTRs, and dark green indicates protein-coding regions. Exons are drawn to scale. Intronic sections are indicated by thin green lines and are not drawn to scale.
Description Transcripts NM_001673, NM_133436, NM_183356, BC008723, BC014621, BT007113, and M27396 encode a common 561 aa (64 kDa) ASNS protein sequence. Transcripts AK302189 and M15798 encode 540 aa N-terminally truncated proteins that differ in sequence between amino acids 312-322 and 332-339. Transcript AK302242 encodes a 478 aa isoform that is further truncated at the N-terminus.
Expression Only the 561 aa isoform has been experimentally confirmed, and it has been found to be up-regulated by nutrient deprivation. Its half-life is reported to be 43-46 h.
Localisation ASNS protein is cytoplasmic, but prediction algorithms also predict a small fraction of nuclear localization.
Function ASNS catalyzes the synthesis of asparagine from glutamine and aspartic acid. In addition to providing asparagine for global protein synthesis, ASNS expression appears to be required for the transition from G1 to S phase of the cell cycle.
Homology The 561 aa ASNS isoform has 29% identity with a protein called asparagine synthetase domain containing 1 (ASNSD1) that is 643 aa in length and encoded by a transcript (NM_019048) produced by chromosome 2.

Mutations

Note A total of 136 SNPs have been reported in the ASNS gene region thus far, and 9 of these are coding SNPs: C1820A (P547H); C1399T (R407X); C1389G (L403L); 1299G (G373-frameshift); G1009A (A277T); T809A (V210E); A546T (A122A); G524C (C115S); C324T (H48H). Of those nine coding SNPs, only V210E has been validated by multiple independent groups including the HapMap Project. None of the SNPs has thus far been clinically associated with a disease or drug response phenotype.
Germinal All reported SNPs appear to be of germline origin.
Somatic None of the reported SNPs have been associated with tumor initiation or progression.

Implicated in

Entity Cancer
Note Chemotherapeutic efficacy of L-asparaginase. The enzyme-drug L-asparaginase has been used since the 1970s to treat acute lymphoblastic leukemia. ASNS expression has been found to be correlated with L-asparaginase efficacy in leukemia cell lines, in leukemia primary tumor samples, and more recently in cancer cell lines from other tissues of origin. Silencing ASNS expression by RNAi has indicated the L-asparaginase/ASNS relationship is causal and suggests that ASNS expression may be useful as a predictive clinical biomarker of L-asparaginase efficacy.
Prognosis Low ASNS expression suggests good response to L-asparaginase.
  
Entity Protein and/or amino acid deprivation
Note The Amino Acid Response (AAR) pathway is triggered by protein and/or amino acid deprivation, which leads to a build up of uncharged tRNA, which bind to and activate the GCN2 kinase, which in turn phosphorylates eIF2alpha. P-eIF2 alpha suppresses global translation initiation yet causes an increase of ATF4 synthesis from preexisting mRNA. ATF4 stimulates transcription of a variety of stress-response genes, including ASNS.
  

External links

Nomenclature
HGNC (Hugo)ASNS   753
Cards
AtlasASNSID44323ch7q21
Entrez_Gene (NCBI)ASNS  440  asparagine synthetase (glutamine-hydrolyzing)
GeneCards (Weizmann)ASNS
Ensembl (Hinxton)ENSG00000070669 [Gene_View]  chr7:97481429-97501854 [Contig_View]  ASNS [Vega]
ICGC DataPortalENSG00000070669
AceView (NCBI)ASNS
Genatlas (Paris)ASNS
WikiGenes440
SOURCE (Princeton)NM_001178075 NM_001178076 NM_001178077 NM_001673 NM_133436 NM_183356
Genomic and cartography
GoldenPath (UCSC)ASNS  -  7q21.3   chr7:97481429-97501854 -  7q21.3   [Description]    (hg19-Feb_2009)
EnsemblASNS - 7q21.3 [CytoView]
Mapping of homologs : NCBIASNS [Mapview]
OMIM108370   615574   
Gene and transcription
Genbank (Entrez)AA948141 AK000379 AK302189 AK302242 AK316224
RefSeq transcript (Entrez)NM_001178075 NM_001178076 NM_001178077 NM_001673 NM_133436 NM_183356
RefSeq genomic (Entrez)AC_000139 NC_000007 NC_018918 NG_033870 NT_007933 NW_001839064 NW_004929332
Consensus coding sequences : CCDS (NCBI)ASNS
Cluster EST : UnigeneHs.489207 [ NCBI ]
CGAP (NCI)Hs.489207
Alternative Splicing : Fast-db (Paris)GSHG0028375
Alternative Splicing GalleryENSG00000070669
Gene ExpressionASNS [ NCBI-GEO ]     ASNS [ SEEK ]   ASNS [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP08243 (Uniprot)
NextProtP08243  [Medical]
With graphics : InterProP08243
Splice isoforms : SwissVarP08243 (Swissvar)
Catalytic activity : Enzyme6.3.5.4 [ Enzyme-Expasy ]   6.3.5.46.3.5.4 [ IntEnz-EBI ]   6.3.5.4 [ BRENDA ]   6.3.5.4 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)GATASE_TYPE_2 (PS51278)   
Domains : Interpro (EBI)Asn_synth_AEB    Asn_synthase    GATase_2_dom    GATase_dom    Ntn_hydrolases_N    Rossmann-like_a/b/a_fold   
Related proteins : CluSTrP08243
Domain families : Pfam (Sanger)Asn_synthase (PF00733)    GATase_7 (PF13537)   
Domain families : Pfam (NCBI)pfam00733    pfam13537   
DMDM Disease mutations440
Blocks (Seattle)P08243
Human Protein AtlasENSG00000070669
Peptide AtlasP08243
HPRD00153
IPIIPI00554777   IPI00925572   IPI00924906   IPI00926480   IPI00925857   IPI00925986   IPI00925298   IPI00927372   IPI00926760   IPI00926959   
Protein Interaction databases
DIP (DOE-UCLA)P08243
IntAct (EBI)P08243
FunCoupENSG00000070669
BioGRIDASNS
IntegromeDBASNS
STRING (EMBL)ASNS
Ontologies - Pathways
QuickGOP08243
Ontology : AmiGOliver development  asparagine synthase (glutamine-hydrolyzing) activity  asparagine synthase (glutamine-hydrolyzing) activity  ATP binding  cytosol  asparagine biosynthetic process  asparagine biosynthetic process  glutamine metabolic process  activation of signaling protein activity involved in unfolded protein response  cellular amino acid biosynthetic process  response to light stimulus  response to mechanical stimulus  response to toxic substance  endoplasmic reticulum unfolded protein response  response to methotrexate  response to follicle-stimulating hormone  cellular response to hormone stimulus  cellular nitrogen compound metabolic process  cellular response to glucose starvation  protein homodimerization activity  negative regulation of apoptotic process  response to amino acid  cellular protein metabolic process  small molecule metabolic process  positive regulation of mitotic cell cycle  cofactor binding  L-asparagine biosynthetic process  
Ontology : EGO-EBIliver development  asparagine synthase (glutamine-hydrolyzing) activity  asparagine synthase (glutamine-hydrolyzing) activity  ATP binding  cytosol  asparagine biosynthetic process  asparagine biosynthetic process  glutamine metabolic process  activation of signaling protein activity involved in unfolded protein response  cellular amino acid biosynthetic process  response to light stimulus  response to mechanical stimulus  response to toxic substance  endoplasmic reticulum unfolded protein response  response to methotrexate  response to follicle-stimulating hormone  cellular response to hormone stimulus  cellular nitrogen compound metabolic process  cellular response to glucose starvation  protein homodimerization activity  negative regulation of apoptotic process  response to amino acid  cellular protein metabolic process  small molecule metabolic process  positive regulation of mitotic cell cycle  cofactor binding  L-asparagine biosynthetic process  
Pathways : KEGGAlanine, aspartate and glutamate metabolism   
REACTOMEP08243 [protein]
REACTOME PathwaysREACT_111217 Metabolism [pathway]
REACTOME PathwaysREACT_17015 Metabolism of proteins [pathway]
Protein Interaction DatabaseASNS
Wikipedia pathwaysASNS
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)ASNS
SNP (GeneSNP Utah)ASNS
SNP : HGBaseASNS
Genetic variants : HAPMAPASNS
1000_GenomesASNS 
ICGC programENSG00000070669 
CONAN: Copy Number AnalysisASNS 
Somatic Mutations in Cancer : COSMICASNS 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
DECIPHER (Syndromes)7:97481429-97501854
Mutations and Diseases : HGMDASNS
OMIM108370    615574   
MedgenASNS
GENETestsASNS
Disease Genetic AssociationASNS
Huge Navigator ASNS [HugePedia]  ASNS [HugeCancerGEM]
Genomic VariantsASNS  ASNS [DGVbeta]
Exome VariantASNS
dbVarASNS
ClinVarASNS
snp3D : Map Gene to Disease440
General knowledge
Homologs : HomoloGeneASNS
Homology/Alignments : Family Browser (UCSC)ASNS
Phylogenetic Trees/Animal Genes : TreeFamASNS
Chemical/Protein Interactions : CTD440
Chemical/Pharm GKB GenePA25052
Clinical trialASNS
Cancer Resource (Charite)ENSG00000070669
Other databases
Probes
Litterature
PubMed61 Pubmed reference(s) in Entrez
CoreMineASNS
GoPubMedASNS
iHOPASNS

Bibliography

Regulation of asparagine synthetase gene expression by amino acid starvation.
Gong SS, Guerrini L, Basilico C.
Mol Cell Biol. 1991 Dec;11(12):6059-66.
PMID 1682798
 
TSH is able to induce cell cycle-related gene expression in rat thyroid cell.
Colletta G, Cirafici AM.
Biochem Biophys Res Commun. 1992 Feb 28;183(1):265-72.
PMID 1543496
 
Activation of the human asparagine synthetase gene by the amino acid response and the endoplasmic reticulum stress response pathways occurs by common genomic elements.
Barbosa-Tessmann IP, Chen C, Zhong C, Siu F, Schuster SM, Nick HS, Kilberg MS.
J Biol Chem. 2000 Sep 1;275(35):26976-85.
PMID 10856289
 
Asparagine synthetase expression alone is sufficient to induce l-asparaginase resistance in MOLT-4 human leukaemia cells.
Aslanian AM, Fletcher BS, Kilberg MS.
Biochem J. 2001 Jul 1;357(Pt 1):321-8.
PMID 11415466
 
Tumor-derived p53 mutants induce oncogenesis by transactivating growth-promoting genes.
Scian MJ, Stagliano KE, Deb D, Ellis MA, Carchman EH, Das A, Valerie K, Deb SP, Deb S.
Oncogene. 2004 May 27;23(25):4430-43.
PMID 15077194
 
An inhibitor of human asparagine synthetase suppresses proliferation of an L-asparaginase-resistant leukemia cell line.
Gutierrez JA, Pan YX, Koroniak L, Hiratake J, Kilberg MS, Richards NG.
Chem Biol. 2006 Dec;13(12):1339-47.
PMID 17185229
 
Asparagine synthetase as a causal, predictive biomarker for L-asparaginase activity in ovarian cancer cells.
Lorenzi PL, Reinhold WC, Rudelius M, Gunsior M, Shankavaram U, Bussey KJ, Scherf U, Eichler GS, Martin SE, Chin K, Gray JW, Kohn EC, Horak ID, Von Hoff DD, Raffeld M, Goldsmith PK, Caplen NJ, Weinstein JN.
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PMID 17088436
 
Asparagine synthetase chemotherapy.
Richards NG, Kilberg MS.
Annu Rev Biochem. 2006;75:629-54.
PMID 16756505
 
Transcriptional induction of the human asparagine synthetase gene during the unfolded protein response does not require the ATF6 and IRE1/XBP1 arms of the pathway.
Gjymishka A, Su N, Kilberg MS.
Biochem J. 2008 Oct 8.
PMID 18840095
 
TRB3 inhibits the transcriptional activation of stress-regulated genes by a negative feedback on the ATF4 pathway.
Jousse C, Deval C, Maurin AC, Parry L, Cherasse Y, Chaveroux C, Lefloch R, Lenormand P, Bruhat A, Fafournoux P.
J Biol Chem. 2007 May 25;282(21):15851-61.
PMID 17369260
 
Asparagine synthetase is a predictive biomarker of L-asparaginase activity in ovarian cancer cell lines.
Lorenzi PL, Llamas J, Gunsior M, Ozbun L, Reinhold WC, Varma S, Ji H, Kim H, Hutchinson AA, Kohn EC, Goldsmith PK, Birrer MJ, Weinstein JN.
Mol Cancer Ther. 2008 Oct;7(10):3123-8.
PMID 18852115
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written11-2008Philip L Lorenzi, Michael C Ryan, Ogechi N Ikediobi, John N Weinstein
Laboratory of Molecular Pharmacology, National Institutes of Health, Bethesda, MD 20892, USA (PLL, MCR); University of California, San Francisco, San Francisco, CA, USA (ONI); M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA (JNW)

Citation

This paper should be referenced as such :
Lorenzi, PL ; Ryan, MC ; Ikediobi, ON ; Weinstein, JN
ASNS (asparagine synthetase)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(10):709-711.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/ASNSID44323ch7q21.html

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indexed on : Sat Nov 8 16:35:12 CET 2014

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