Atlas of Genetics and Cytogenetics in Oncology and Haematology
ASNS (asparagine synthetase)
| Identity |
| Other names | TS11 |
| 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 |
| 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. |
| Mol Cancer Ther. 2006 Nov;5(11):2613-23. |
| 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 articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| Contributor(s) |
| Written | 11-2008 | Philip 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. November 2008 . URL : http://AtlasGeneticsOncology.org/Genes/ASNSID44323ch7q21.html |
This paper is referenced by INIST as such : |
| http://documents.irevues.inist.fr/bitstream/2042/44576/1/11-2008-ASNSID44323ch7q21.pdf [ Bibliographic record ] |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Wed May 1 12:57:06 CEST 2013 |
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