Glutathione S-transferases ( GSTs ) are expressed in many beings. They are involved in contact action of the junction of glutathione ( GSH ) with assorted electrophilic compounds. They besides play an of import function in detoxification of xenobiotics. In general GSTs have been found to be involved in the supplying opposition to chemotherapeutic agents and in signaling tract ordinance that helps in control of malignant neoplastic disease cell endurance and cell decease [ 1 ] . GSTs are grouped under stage II metabolizing enzymes superfamily. They besides play an of import function in detoxification of ROS and care of the cellular oxidation-reduction province [ 10 ] . Although GSTs were early investigated because of their enzymatic activity involved in the junction of GSH to a broad scope of electrophilic metabolites and effects on protecting tumour cells against toxic drugs and oxidative emphasis, they were so discovered as ‘ligandins ‘ owing to their abilities to interact covalently and non-covalently with assorted compounds that were non substrates for enzymatic activity, including steroids, thyroid endocrines, hematoidin, prostaglandins and bile acid [ 10 ] .
GSTP-1 & A ; Cancer:
Chemotherapeutic agent immune human tumour cell lines over express category pi GST ( GSTP-1 ) . Cancers such as ovarian, lung, kidney, colon and chest malignant neoplastic disease normally involve high look of GSTP-1 compared to environing tissues [ 1 ] .
GSTP-1 has been shown to be involved in the suppression of c-Jun N-terminal kinase ( JNK ) through direct protein-protein interaction. JNK is a mitogen-activated protein kinase that is involved in programmed cell death, cell distinction, redness and proliferation. Activated JNK phosphorylates c-Jun, a constituent of the Activator Protein-1 ( AP-1 ) written text factor. This activation causes initiation of AP-1-dependent mark cistrons that lead to cell proliferation or cell decease [ 1 ] .
GSTP1-1 has besides been reported to tie in with tumour mortification factor receptor-associated factor2 ( TRAF2 ) and inhibit TRAF2-induced activation of both JNK and p38-MAPK. GSTP1-1inhibited TRAF2-enhanced programmed cell death signal-regulating kinase 1 ( ASK1 ) auto-phosphorylation andTRAF2-ASK1-induced cell programmed cell death [ 1 ] .
Features of GSTP-1:
Synonym: FAEES3, GST3, DFN7, PI
Venue: 11q13.2 [ 12 ]
Sequence length: 210 AA.
GSTP-1 has two spheres viz. GST N-terminal ( Position: 2-81 ; Length: 80 ) and GST C-terminal ( Position: 83-204 ; Length: 122 )
Function: Junction of decreased glutathione to no. of endogenous and exogenic hydrophobic electrophiles [ 6, 9 ] .
Function of GSTP-1:
GSTs have been found to be involved in the biogenesis and metamorphosis of prostaglandins, steroids and leukotrienes. They play an of import function in transition of cell signaling and control of cell proliferation and programmed cell death. They are besides involved in the direction of toxic merchandises of lipid oxidization and S-glutathiolated proteins generated by oxidative emphasis [ 2 ] .
GSTP-1 and JNK cascade:
GSTP-1 in cell signaling [ 2 ]
Harmonizing to surveies, under non-stressed conditions, GSTP1 monomer inhibits c-Jun N-Terminal kinase ( JNK ) through formation of a protein composite. JNK or emphasis activated kinase, belongs to the mitogen emphasis kinase household ( MAPK ) , which besides includes extracellular signal regulated kinase and p38-MAPK [ 14 ] . Happening of oxidative emphasis causes GSTP1 to disassociate from JNK and subsequent formation of inactive covalent dimers. Under these conditions, full JNK activity is restored by JNK taking to activation of c-Jun through phosphorylation at Ser-63 or Ser-73 residues and increased written text of AP-1-responsive cistrons. This consequences in activation of signaling tracts for emphasis response, proliferation and programmed cell death. Surveies besides suggest that reactive O species ( ROS ) -generating agents activate GSTP1 written text via the JNK/Jun cascade and organize a elusive regulative cringle dependant on the continuance and magnitude of stress kinase activity. Through transcriptionally active JNK substrates, including c-Jun, new synthesis of GSTP1 occurs, which is expected to restart JNK suppression. Therefore, GSTP1 influences signaling tracts for programmed cell death by modulating JNK kinase activity [ 3 ] .
GSTP-1 and TRAF2:
Tumor mortification factor-I± ( TNF-I± ) is a cytokine that is widely involved in activation of written text factors. Tumor mortification factor receptor associated factor 2 ( TRAF2 ) is a member of the TRAF household, which is a signal transducer for the TNF receptor household [ 10 ] . Stimulation of the receptor TNF-R1 leads to the enlisting of the adapter TRAF2 and coincident activation of a phosphatase mechanism. The association of programmed cell death signal-regulating kinase 1 ( ASK1 ) with AIP1 is mediated by TRAF2. As a consequence ASK1 is released from its endogenous inhibitor 14-3-3 and coincident de-phosphorylation occurs ( fig. ) . ASK1 now activates the c-Jun NH2- terminus kinase ( JNK ) via MKK4 or MKK6 dependent tract. Activated JNK is involved in ordinance of programmed cell death. GSTP1 inhibits TNF- I± induced TRAF2-ASK1-JNK cascade activation and cell programmed cell death. GSTP1 competes with ASK1 for adhering to the TRAF sphere of TRAF2 [ 11 ] . Subjects with the combination of GSTM1 nothing and GSTP1 AG or GG genotypes are more susceptible to smoking-induced redness than those with the other genotype combinations [ 16 ] .
Consequence of Carcinogens on GSTP-1:
A no. of surveies has shown the association between active smoke and lung malignant neoplastic disease hazard by familial polymorphisms. Genes involved in Phase I and II metamorphosis are involved straight in the metamorphosiss of baccy fume carcinogens ( BaP, PAH etc. ) . Glutathione S-transferases, a major group of enzymes, whose chief categories are I± , Aµ , Iˆ and I? , are straight involved in the detoxification measure of metamorphosis ( Phase II ) . The look of these enzymes differs among variety meats. GST Iˆ has the highest look in the lung and is one of the chief detoxifiers of the activated signifier of benzopyrene, a major carcinogen of baccy fume. GST Iˆ is encoded by a polymorphous cistron, GSTP1. The polymorphism in GSTP1 occurs as a consequence of a individual base brace permutation, where A is replaced by G ( A313G ) , taking to an amino acid permutation in which Isoleucine ( I105 ) is replaced by Valine ( V105 ) . This permutation consequences in a lower enzymatic activity, and is associated with higher hydrophobic adduct degrees in lung tissue and higher degrees of PAH-DNA adducts in human lymph cells [ 4 ] .
The work of Ali-Osman et Al. ( 1997 ) involved isolation of complementary DNA matching to 3 polymorphous GSTP1 allelomorphs, GSTP1*A, GSTP1*B, and GSTP1*C as a consequence of A-to-G and C-to-T passages at bases 313 and 341, severally. The passages changed codon 105 from ATC ( ile ) in GSTP1*A to GTC ( val ) in GSTP1*B and GSTP1*C, and changed codon 114 from GCG ( ala ) to GTG ( val ) in GSTP1*C. Both amino acid alterations are in the electrophile-binding active site of the GST-pi peptide [ 7 ] .
GSTP-1 and lung Cancer:
Harmonizing to a survey the most common lung tumour is squamous cell carcinoma in the instance of work forces and glandular cancer in adult females. GSTP1 chiefly detoxifies the polycyclic aromatic hydrocarbons present in coffin nail fume [ 8 ] . It was determined in the survey that GSTP1 exon5 ( ile105val ) polymorphism is associated with the addition in lung malignant neoplastic disease hazard by about 7.5 times higher in persons who have homozygote allele G [ 5 ] . Exon 5 GSTP1 familial polymorphism occurs in 3 bing genotypes: GSTP1*A/*A ( Ile/Ile ) , GSTP1*A/*B ( Ile/Val ) and GSTP1*B/*B ( Val/Val ) . Another well-known familial polymorphism of GSTP1 is connected with Ala to Val alteration at codon 114 [ 13 ] .
GSTP1 and malignant neoplastic disease of Pharynx and Oral pit:
A survey supported the position that GSTP1 polymorphism is involved in modulating the susceptibleness to malignant neoplastic diseases of unwritten pit and throat. GSTP1 ( AG or GG ) genotype was found to present a 2 fold addition in hazard of malignant neoplastic disease [ 14 ] .