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ASNS (asparagine synthetase)
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)
Published in Atlas Database: November 2008
Online updated version : http://AtlasGeneticsOncology.org/Genes/ASNSID44323ch7q21.html
DOI: 10.4267/2042/44576
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology
DNA/RNA
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.
Description
Protein
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.
Description
Identity
Other names: TS11
HGNC (Hugo): ASNS
Location: 7q21.3
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.
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 NSRE1 and/or NSRE-2. TRB3 is a negative feedback
regulator of ATF4-dependent transcription, and C/EBPbeta is a negative regulator of ATF5-dependent
transcription. DDIT3/CHOP is also a negative regulator
of ASNS
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(10)
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
709
ASNS (asparagine synthetase)
Lorenzi PL, et al.
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.
providing asparagine for global protein synthesis,
ASNS expression appears to be required for the
transition from G1 to S phase of the cell cycle.
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 Lasparaginase/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 Lasparaginase.
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
Protein and/or amino acid deprivation
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.
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.
References
Germinal
Gong SS, Guerrini L, Basilico C. Regulation of asparagine
synthetase gene expression by amino acid starvation. Mol Cell
Biol. 1991 Dec;11(12):6059-66
All reported SNPs appear to be of germline origin.
Somatic
Colletta G, Cirafici AM. TSH is able to induce cell cycle-related
gene expression in rat thyroid cell. Biochem Biophys Res
Commun. 1992 Feb 28;183(1):265-72
None of the reported SNPs have been associated with
tumor initiation or progression.
Barbosa-Tessmann IP, Chen C, Zhong C, Siu F, Schuster SM,
Nick HS, Kilberg MS. Activation of the human asparagine
synthetase gene by the amino acid response and the
endoplasmic reticulum stress response pathways occurs by
common genomic elements. J Biol Chem. 2000 Sep
1;275(35):26976-85
Implicated in
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-
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(10)
Aslanian AM, Fletcher BS, Kilberg MS. Asparagine synthetase
expression alone is sufficient to induce l-asparaginase
resistance in MOLT-4 human leukaemia cells. Biochem J.
2001 Jul 1;357(Pt 1):321-8
710
ASNS (asparagine synthetase)
Lorenzi PL, et al.
Scian MJ, Stagliano KE, Deb D, Ellis MA, Carchman EH, Das
A, Valerie K, Deb SP, Deb S. Tumor-derived p53 mutants
induce oncogenesis by transactivating growth-promoting
genes. Oncogene. 2004 May 27;23(25):4430-43
Chaveroux C, Lefloch R, Lenormand P, Bruhat A, Fafournoux
P. TRB3 inhibits the transcriptional activation of stressregulated genes by a negative feedback on the ATF4 pathway.
J Biol Chem. 2007 May 25;282(21):15851-61
Gutierrez JA, Pan YX, Koroniak L, Hiratake J, Kilberg MS,
Richards NG. An inhibitor of human asparagine synthetase
suppresses proliferation of an L-asparaginase-resistant
leukemia cell line. Chem Biol. 2006 Dec;13(12):1339-47
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. Asparagine synthetase is a
predictive biomarker of L-asparaginase activity in ovarian
cancer cell lines. Mol Cancer Ther. 2008 Oct;7(10):3123-8
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. Asparagine
synthetase as a causal, predictive biomarker for Lasparaginase activity in ovarian cancer cells. Mol Cancer Ther.
2006 Nov;5(11):2613-23
Gjymishka A, Su N, Kilberg MS. 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. Biochem J. 2009 Feb 1;417(3):695-703
This article should be referenced as such:
Richards
NG, Kilberg MS. Asparagine synthetase
chemotherapy. Annu Rev Biochem. 2006;75:629-54
Lorenzi PL, Ryan MC, Ikediobi ON, Weinstein JN. ASNS
(asparagine synthetase). Atlas Genet Cytogenet Oncol
Haematol. 2009; 13(10):709-711.
Jousse C, Deval C, Maurin AC, Parry L, Chérasse Y,
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(10)
711