Identification and Functional Characterization of the Human <i>Glutathione S-Transferase P1</i> Gene as a Novel Transcriptional Target of the <i>p53</i> Tumor Suppressor Gene

Lo, Hui-Wen; Stephenson, Lisa P.; Cao, Xinyu; Milas, Mira; Pollock, Raphael E.; Ali‐Osman, Francis

doi:10.1158/1541-7786.mcr-07-2105

Cited by 54 publications

(37 citation statements)

References 35 publications

(38 reference statements)

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“…In contrast to mice, GSTP expression is restricted to the biliary epithelium in normal human liver. A number of transcription binding sites, such as AP-1 (Moffat et al, 1997), p53 (Lo et al, 2008), retinoic acid, and nuclear factor kB (Xia et al, 1993), have been identified within the human GSTP gene. Recently, we have made further efforts to characterize the regulation of human GSTP1 in an animal model and demonstrated upregulation of human hepatic GSTP expression in response to the chemopreventive agents ethoxyquin and butylated hydroxyanisole (Henderson et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Altered ProteinS-Glutathionylation Identifies a Potential Mechanism of Resistance to Acetaminophen-Induced Hepatotoxicity

McGarry

Chakravarty

Wolf

et al. 2015

J Pharmacol Exp Ther

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Acetaminophen (APAP) is the most commonly used over-thecounter analgesic. However, hepatotoxicity induced by APAP is a major clinical issue, and the factors that define sensitivity to APAP remain unclear. We have previously demonstrated that mice nulled for glutathione S-transferase Pi (GSTP) are resistant to APAP-induced hepatotoxicity. This study aims to exploit this difference to delineate pathways of importance in APAP toxicity. We used mice nulled for GSTP and heme oxygenase-1 oxidative stress reporter mice, together with a novel nanoflow liquid chromatography-tandem mass spectrometry methodology to investigate the role of oxidative stress, cell signaling, and protein S-glutathionylation in APAP hepatotoxicity. We provide evidence that the sensitivity difference between wild-type and Gstp1/2 2/2 mice is unrelated to the ability of APAP to induce oxidative stress, despite observing significant increases in c-Jun N-terminal kinase and extracellular signal-regulated kinase phosphorylation in wildtype mice. The major difference in response to APAP was in the levels of protein S-glutathionylation: Gstp1/2 2/2 mice exhibited a significant increase in the number of S-glutathionylated proteins compared with wild-type animals. Remarkably, these S-glutathionylated proteins are involved in oxidative phosphorylation, respiratory complexes, drug metabolism, and mitochondrial apoptosis. Furthermore, we found that S-glutathionylation of the rate-limiting glutathione-synthesizing enzyme, glutamate cysteine ligase, was markedly increased in Gstp1/2 2/2 mice in response to APAP. The data demonstrate that S-glutathionylation provides an adaptive response to APAP and, as a consequence, suggest that this is an important determinant in APAP hepatotoxicity. This work identifies potential novel avenues associated with cell survival for the treatment of chemical-induced hepatotoxicity.

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Section: Discussionmentioning

confidence: 99%

Altered ProteinS-Glutathionylation Identifies a Potential Mechanism of Resistance to Acetaminophen-Induced Hepatotoxicity

McGarry

Chakravarty

Wolf

et al. 2015

J Pharmacol Exp Ther

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“…This in vivo evidence is unique in showing that Gstp can alter tumorigenicity in a model that does not involve carcinogens, and suggests that variation in GSTP expression could influence colon cancer susceptibility. Human GSTP can be regulated by a number of pathways including AP1, retinoic acid, and p53 signaling (17)(18)(19). Using a mouse humanized for the Gstp gene, we are currently investigating whether GSTP can be regulated in the colon by chemopreventative agents such as ethoxyquin, butylated hydroxyanisole, and sulforaphane.…”

Section: Discussionmentioning

confidence: 99%

Markedly enhanced colon tumorigenesis in Apc ^Min mice lacking glutathione S-transferase Pi

Ritchie

Walsh

Sansom

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Glutathione transferases are a multigene family of proteins that catalyze the conjugation of toxic electrophiles and carcinogens to glutathione. Glutathione transferase Pi (GSTP) is commonly overexpressed in human tumors and there is emerging evidence that the enzyme has additional cellular functions in addition to its role in drug and carcinogen detoxification. To investigate the unique functions of this enzyme, we have crossed Gstp null mice with an initiated model of colon cancer, the Apc Min mouse. In contrast to the Apc Min/؉ Gstp1/p2 ؉/؉ (Gstp-wt Apc Min ) mice, which rarely develop colonic tumours, Apc Min/؉ Gstp1/p2 ؊/؊ (Gstp-null Apc Min ) mice had a 6-fold increase in colon adenoma incidence, and a 50-fold increase in colorectal adenoma multiplicity, relative to Gstp-wt Apc Min . This increase was associated with early tumor onset and decreased survival. Analysis of the biochemical changes in the colon tissue of Gstp-null Apc Min mice demonstrated a marked induction of many inflammatory genes, including IL-6, IL-4, IFN-␥, and inducible nitric oxide synthase. In support of the induction of inducible nitric oxide synthase, a profound induction of nitrotyrosine adducts was observed. Gstp therefore appears to play a role in controlling inflammatory responses in the colon, which would explain the change in tumor incidence observed. These data also suggest that individual variation in GSTP levels may be a factor in colon cancer susceptibility.cancer ͉ colorectal ͉ inflammation G lutathione S-transferases play a key role in chemical detoxification by catalyzing the conjugation of reduced glutathione to reactive electrophiles (1). In a genetic approach to study GST functions, we have generated mice nulled at the glutathione transferase Pi (GSTP) Gstp gene locus (2). These mice develop normally, are fertile, and show no obvious abnormalities. Topical application of the tumor initiator 7,12-dimethylbenz[a]anthracene, followed by the promoting agent 12-0-tetradecanoylphorbol-13-acetate, resulted in a significant increase in the number of papillomas in null animals (2). Similarly, increased adenoma formation in the lungs of Gstp-null mice relative to wild-type mice was also observed following dosing with benzo[a]pyrene, 3-methylcholanthene and urethane (3). In recent studies we have obtained evidence that this protein can also modulate toxicological or carcinogenic response in a manner distinct from its role in chemical detoxification (4). Further evidence of unique GSTP function is demonstrated by its ability to form protein-protein interactions and regulate the activities of several cellular proteins (JNK and TRAF2) independently of its catalytic function (5, 6). GSTP has also been shown to potentiate S-glutathionylation reactions following oxidative and nitrosative stress in vitro and in vivo (7).To further evaluate the role of GSTP in disease processes, we have investigated whether GSTP can alter colon cancer susceptibility in the Apc Min mouse. Mutations in the Apc gene is a major initiating factor in the aet...

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“…Recently GST has been identified as an endogenous protein binding partner and regulator of c-Jun NH 2 -terminal kinase (JNK) and peroxiredoxin VI (1-cysPrx) (4 -6). Moreover, oxidative stress causes increased GST expression, the regulation of which has been identified as a downstream event linked to wild-type p53 function (7). Cellular response to oxidative or nitrosative stress includes S-glutathionylation, a post-translational modification characterized by conjugation of glutathione to low pK cysteine sulfhydryl or sulfenic acid moieties in target proteins.…”

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confidence: 99%

Novel Role for Glutathione S-Transferase π

Townsend

Manevich

et al. 2009

Journal of Biological Chemistry

271

136

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Glutathione S-transferase Pi (GST ) is a marker protein in many cancers and high levels are linked to drug resistance, even when the selecting drug is not a substrate. S-Glutathionylation of proteins is critical to cellular stress response, but characteristics of the forward reaction are not known. Our results show that GST potentiates S-glutathionylation reactions following oxidative and nitrosative stress in vitro and in vivo. Mutational analysis indicated that the catalytic activity of GST is required. GST is itself redox-regulated. S-Glutathionylation on Cys 47 and Cys 101 autoregulates GST , breaks ligand binding interactions with c-Jun NH 2 -terminal kinase (JNK), and causes GST multimer formation, all critical to stress response. Catalysis of S-glutathionylation at low pK cysteines in proteins is a novel property for GST and may be a cause for its abundance in tumors and cells resistant to a range of mechanistically unrelated anticancer drugs.Glutathione S-transferases (GSTs) 2 are classified as a family of Phase II detoxification enzymes that have classically been described as catalyzing the conjugation of glutathione (GSH) to electrophilic compounds through thioether linkages (1). The Pi class (GST ) is present at high levels in many solid tumors (particularly ovarian, non-small cell lung, breast, liver, pancreas, colon, and lymphomas) and has been indicated in many reports to be overexpressed in drug-resistant tumors (2, 3). Although its increased expression was frequently linked with enhancement of drug detoxification, in most instances the selecting drugs were not substrates of GST . This ambiguity and the high prevalence of GST in tumors have intimated cellular functions for the protein that are unrelated to catalytic detoxification. Recently GST has been identified as an endogenous protein binding partner and regulator of c-Jun NH 2 -terminal kinase (JNK) and peroxiredoxin VI (1-cysPrx) (4 -6). Moreover, oxidative stress causes increased GST expression, the regulation of which has been identified as a downstream event linked to wild-type p53 function (7). Cellular response to oxidative or nitrosative stress includes S-glutathionylation, a post-translational modification characterized by conjugation of glutathione to low pK cysteine sulfhydryl or sulfenic acid moieties in target proteins. This adds a three-amino acid side chain and introduces a net negative charge (as a consequence of glutamic acid) to the protein (8). Consequently, protection from further oxidative damage and/or alteration of protein conformation affecting function and/or cellular localization occurs. Proteins so far identified that are susceptible to S-glutathionylation can be categorized into six distinct clusters: cytoskeletal, glycolysis/energy metabolism, kinases and signaling pathways, calcium homeostasis, antioxidant enzymes, and protein folding (9). Reversibility of S-glutathionylation spontaneously by GSH or catalytically by glutaredoxin or sulfiredoxin (8, 10) 3 provides the cell with a dynamic cycle of regulatory events....

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Identification and Functional Characterization of the Human Glutathione S-Transferase P1 Gene as a Novel Transcriptional Target of the p53 Tumor Suppressor Gene

Cited by 54 publications

References 35 publications

Altered ProteinS-Glutathionylation Identifies a Potential Mechanism of Resistance to Acetaminophen-Induced Hepatotoxicity

Altered ProteinS-Glutathionylation Identifies a Potential Mechanism of Resistance to Acetaminophen-Induced Hepatotoxicity

Markedly enhanced colon tumorigenesis in Apc ^Min mice lacking glutathione S-transferase Pi

Novel Role for Glutathione S-Transferase π

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Identification and Functional Characterization of the Human Glutathione S-Transferase P1 Gene as a Novel Transcriptional Target of the p53 Tumor Suppressor Gene

Cited by 54 publications

References 35 publications

Altered ProteinS-Glutathionylation Identifies a Potential Mechanism of Resistance to Acetaminophen-Induced Hepatotoxicity

Altered ProteinS-Glutathionylation Identifies a Potential Mechanism of Resistance to Acetaminophen-Induced Hepatotoxicity

Markedly enhanced colon tumorigenesis in Apc Min mice lacking glutathione S-transferase Pi

Novel Role for Glutathione S-Transferase π

Contact Info

Product

Resources

About

Markedly enhanced colon tumorigenesis in Apc ^Min mice lacking glutathione S-transferase Pi