Disease relevance of GSTA2

• The variant isoforms of GSTA2 were expressed in Escherichia coli, purified, and enzymatically characterized [1].
• Using a prostate cancer case-control population, it was found that GSTA1*A/GSTA2 C335 and GSTA1*B/GSTA2 G335 were in linkage disequilibrium in Caucasians but not in African-Americans [2].
• We show that functional human GSH S-transferases 1-1 and 2-2 are synthesized from lambda gt11 cDNA clones lambda GTH1 and lambda GTH2 in phage lysates of E. coli Y1090, in lysogens of E. coli Y1089, and from the plasmid expression constructs in pKK223-3 [3].

High impact information on GSTA2

• The deduced amino acid sequence is rich in lysine, which is consistent with the relatively high pI of GST-2 [4].
• By contrast, treatment with the proteasome inhibitors (lactacystin or MG-132) caused an accumulation of Nrf2 as well as an induction of reporter gene activity in cells transfected with the GSTA2 antioxidant response element-chloramphenicol acetyl transferase construct [5].
• Treatment with 30 microm H(2)O(2) for 48 h or 40 microm PC-OOH for 8 h causes apoptosis in control cells, whereas hGSTA2-2-overexpressing cells are protected from apoptosis under these conditions [6].
• Role of glutathione S-transferases in protection against lipid peroxidation. Overexpression of hGSTA2-2 in K562 cells protects against hydrogen peroxide-induced apoptosis and inhibits JNK and caspase 3 activation [6].
• This study examined whether oltipraz induces phosphorylation of C/EBPbeta at specific residues, and if so, whether RSK1 regulates C/EBPbeta phosphorylation by oltipraz for the GSTA2 gene transactivation [7].

Biological context of GSTA2

• We detected an upregulation of GSTs (GSTA2, GSTT2) that are known to be involved in the defence against oxidative stress in primary cells upon incubation with butyrate [8].
• Nevertheless, the rare genotypes, GSTA2*E/*E and GSTA1*B/*B + GSTA2*C/*C (potential low GSTA2 activity and low hepatic GSTA1 and GSTA2 expression, respectively) could increase the risk of adverse effects of xenobiotics via compromised efficiency of detoxification [2].
• Polymerase chain reaction/restriction fragment length polymorphism analysis revealed the existence of three variants, a silent base substitution, K125K (G365A) in GSTA1, and T112S and E210A in GSTA2, in European Australian, African and Chinese populations [1].
• A genetic polymorphism in the 5'-regulatory sequence of hGSTA1 has been shown to correlate with the relative and absolute levels of expression of GSTA1/GSTA2 in human liver [9].
• Constructs consisting of the proximal promoters of hGSTA1*A, hGSTA1*B or hGSTA2, with luciferase as a reporter gene, showed differential expression when transfected into HepG2 cells: hGSTA1*A approximately hGSTA2 > hGSTA1*B [10].

Anatomical context of GSTA2

• GSTA1 and GSTA2 were expressed at high levels in duodenum and small intestine and expression decreased from proximal to distal small intestine [11].
• Two distinct cDNAs corresponding to GSTA1 and GSTA2 genes encoding glutathione S-transferases (GSTs) from the hepatopancreas of red sea bream, Pagrus major were cloned and sequenced [12].
• HLE B-3 cell membranes were prepared, peroxidized, and used to examine whether hGSTA1-1 and hGSTA2-2 catalyzes the reduction of membrane PL-OOH in situ using the microiodometric and spectrophotometric assays [13].
• Compared to parental MCF-7 or pSV2neotransfected control cell lines, covalent labeling of total cellular macromolecules by [3H]NQO (0.1-1.0 mM) was reduced by 70% and 92% in hGSTP1-1- and mGSTM1-1-transfected cell lines, respectively, but was not affected in the hGSTA2-2 expressing line [14].
• The GST2 isozymes are not detectable in erythrocytes, platelets, cultured fibroblasts or lymphocytoid cells but are found in many other tissues, including fetal liver [15].

Associations of GSTA2 with chemical compounds

• A cluster of three glutathione S-transferase genes, designated GSTA, GSTA1 and GSTA2, was isolated from the marine flatfish, plaice (Pleuronectes platessa) [16].
• The results indicate that human GSTA2 facilitates the protection of cells from HN2 damage and not repair [17].
• We have isolated the 5'flanking regions of two human Alpha class glutathione S-transferase genes, GSTA1 and GSTA2 [18].
• Our results demonstrate for the first time that hGSTA1-1 and hGSTA2-2 effectively catalyzed GSH-dependent reduction of membrane PL-OOH in situ in HLE B-3 cells [13].
• Transfection with hGSTA1 or hGSTA2 protected these cells from H2O2- and naphthalene-induced LPO and attenuated H2O2- and naphthalene-induced apoptosis through inhibiting caspase 3 activation [13].

Physical interactions of GSTA2

• These results suggest that PXR interacts with factors binding to the ARE to elicit the pregnane inductive response for GSTA2 [19].

Regulatory relationships of GSTA2

• High concentrations of the glucocorticoid receptor (GR) antagonist RU38486 (5--10 microM) also induced the expression of GSTA2 [19].

Other interactions of GSTA2

• Conversely, mean hGSTA2 expression increased according to the same order of hGSTA1 genotype [10].
• In order to relate the in vivo BIU pharmacokinetics to the activity of glutathione S-transferase (GST) isoenzymes, the GSH conjugation of BIU enantiomers was studied with human liver and intestinal cytosolic fractions as well as purified human class alpha (GSTA1-1, GSTA2-2), mu (GSTM1a-1a) and pi (GSTP1-1) GST isoenzymes [20].
• Other steroids of the pregnane class induced GSTA2 expression as expected for a PXR-dependent process [19].
• Role of p90 ribosomal S6-kinase-1 in oltipraz-induced specific phosphorylation of CCAAT/enhancer binding protein-beta for GSTA2 gene transactivation [7].
• The activity with cumene hydroperoxide may reflect a diminished physiological function since the glutathione peroxidase activity of GSTA2-2 plays a role in prostaglandin synthesis [21].

Analytical, diagnostic and therapeutic context of GSTA2

• Immunoprecipitation-immunoblot, chromatin-immunoprecipitation, and specific mutation analyses revealed that Ser(105)-phosphorylated C/EBPbeta recruited the cAMP response element-binding protein binding protein for histone acetylation and transactivation of the GSTA2 gene [7].

References