1. Gene Aliases

Glutathione Peroxidase 2, GSHPX-GI, Glutathione Peroxidase 2 (Gastrointestinal), Glutathione Peroxidase-Related Protein 2, Gastrointestinal Glutathione Peroxidase, Selenoprotein GPX2, GSHPx-2, GPRP-2, GPx-GI, GPx-2, Glutathione Peroxidase-Gastrointestinal, GSHPx-GI, GI-GPx, GPRP

[https://www.genecards.org/cgi-bin/carddisp.pl?gene=GPX2&keywords=Gpx2#aliases_descriptions]

2. Association with Toxicity and/or Disease at a Transcriptional Level

3. Summary of Protein Family and Structure

4. Proteins Known to Interact with Gene Product

Interactions with experimental support

Interactions with text mining support

5. Links to Gene Databases

6. GO Terms, MSigDB Signatures, Pathways Containing Gene with Descriptions of Gene Sets

Pathways:

Synthesis of 12-eicosatetraenoic acid derivatives: The 12-eicosatetraenoic acids: 12-hydroperoxy-eicosatetraenoic acid (12-HpETE), 12-hydroxyeicosatetraenoic acid (12-HETE) and 12-oxo-eicosatetraenoic acid (12-oxoETE) are formed after the initial step of arachidonic acid oxidation by the arachidonate 12 and 15 lipoxygenases (ALOX12, ALOX12B and ALOX15 respectively). This part of the pathway is bifurcated at the level of 12S-hydroperoxy-eicosatetraenoic acid (12S-HpETE), which can either be reduced to 12S-hydro-eicosatetraenoic acid (12S-HETE) or converted to hepoxilins [https://reactome.org/PathwayBrowser/#/R-HSA-2142712].

Synthesis of 15-eicosatetraenoic acid derivatives: The 15-eicosatetraenoic acids: 15-hydroperoxy-eicosatetraenoic acid (15-HpETE), 15-hydroxyeicosatetraenoic acid (15-HETE) and 15-oxo-eicosatetraenoic acid (15-oxoETE) are formed after the initial step of arachidonic acid oxidation by the arachidonate 15-lipoxygenases (ALOX15 and ALOX15B) [https://reactome.org/PathwayBrowser/#/R-HSA-2142770].

Synthesis of 5-eicosatetraenoic acids: 5-hydroperoxy-eicosatetraenoic acid (5-HpETE), 5-hydroxyeicosatetraenoic acid (5S-HETE) and 5-oxo-eicosatetraenoic acid (5-oxoETE) are formed after the initial step of arachidonic acid oxidation by arachidonate 5-lipoxygenase (ALOX5) [https://reactome.org/PathwayBrowser/#/R-HSA-2142688].

Detoxification of Reactive Oxygen Species: Reactive oxygen species such as superoxide (O2.-), peroxides (ROOR), singlet oxygen, peroxynitrite (ONOO-), and hydroxyl radical (OH.) are generated by cellular processes such as respiration (reviewed in Murphy 2009, Brand 2010) and redox enzymes and are required for signaling yet they are damaging due to their high reactivity (reviewed in Imlay 2008, Buettner 2011, Kavdia 2011, Birben et al. 2012, Ray et al. 2012). Aerobic cells have defenses that detoxify reactive oxygen species by converting them to less reactive products. Superoxide dismutases convert superoxide to hydrogen peroxide and oxygen (reviewed in Fukai and Ushio-Fukai 2011). Catalase and peroxidases then convert hydrogen peroxide to water [https://reactome.org/PathwayBrowser/#/R-HSA-3299685].

TP53 Regulates Metabolic Genes: While the p53 tumor suppressor protein (TP53) is known to inhibit cell growth by inducing apoptosis, senescence and cell cycle arrest, recent studies have found that p53 is also able to influence cell metabolism to prevent tumor development. TP53 regulates transcription of many genes involved in the metabolism of carbohydrates, nucleotides and amino acids, protein synthesis and aerobic respiration [https://reactome.org/PathwayBrowser/#/R-HSA-5628897].

Signaling by WNT: WNT signaling pathways control a wide range of developmental and adult process in metozoans including cell proliferation, cell fate decisions, cell polarity and stem cell maintenance (reviewed in Saito-Diaz et al, 2013; MacDonald et al, 2009). The pathway is named for the WNT ligands, a large family of secreted cysteine-rich glycoproteins [https://reactome.org/PathwayBrowser/#/R-HSA-195721].

GO terms:

biological process involved in interaction with symbiont [An interaction between two organisms living together in more or less intimate association. The term symbiont is used for the smaller (macro) of the two members of a symbiosis; the various forms of symbiosis include parasitism, commensalism and mutualism. GO:0051702]

cellular oxidant detoxification [Any process carried out at the cellular level that reduces or removes the toxicity superoxide radicals or hydrogen peroxide. GO:0098869]

negative regulation of inflammatory response to antigenic stimulus [Any process that stops, prevents, or reduces the frequency, rate, or extent of an inflammatory response to an antigenic stimulus. GO:0002862]

response to oxidative stress [Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of oxidative stress, a state often resulting from exposure to high levels of reactive oxygen species, e.g. superoxide anions, hydrogen peroxide (H2O2), and hydroxyl radicals. GO:0006979]

response to salicylic acid [Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a salicylic acid stimulus. GO:0009751]

response to selenium ion [Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stimulus from selenium ion. GO:0010269]

response to symbiotic bacterium [Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stimulus from a symbiotic bacterium, a bacterium living in close physical association with another organism. GO:0009609]

temperature homeostasis [A homeostatic process in which an organism modulates its internal body temperature. GO:0001659]

MSigDB Signatures:

ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_UP: Genes up-regulated in normal tissue adjacent to liver tumor, compared to the normal liver samples. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_UP.html]

WP_ONE_CARBON_METABOLISM_AND_RELATED_PATHWAYS: One carbon metabolism and related pathways [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_ONE_CARBON_METABOLISM_AND_RELATED_PATHWAYS.html]

REACTOME_METABOLISM_OF_LIPIDS: Metabolism of lipids [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_METABOLISM_OF_LIPIDS.html]

REACTOME_FATTY_ACID_METABOLISM: Fatty acid metabolism [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_FATTY_ACID_METABOLISM.html]

CHIANG_LIVER_CANCER_SUBCLASS_POLYSOMY7_DN: Marker genes down-regulated in the 'chromosome 7 polysomy' subclass of hepatocellular carcinoma (HCC); characterized by polysomy of chromosome 7 and by a lack of gains of chromosome 8q. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/CHIANG_LIVER_CANCER_SUBCLASS_POLYSOMY7_DN.html]

HOSHIDA_LIVER_CANCER_SURVIVAL_UP: Survival signature genes defined in adjacent liver tissue: genes correlated with poor survival of hepatocellular carcinoma (HCC) patients. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/HOSHIDA_LIVER_CANCER_SURVIVAL_UP.html]

WP_METAPATHWAY_BIOTRANSFORMATION_PHASE_I_AND_II: Metapathway biotransformation Phase I and II [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_METAPATHWAY_BIOTRANSFORMATION_PHASE_I_AND_II.html]

WP_TRANS_SULFURATION_ONE_CARBON_METABOLISM_AND_RELATED_PATHWAYS: Trans sulfuration one carbon metabolism and related pathways [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_TRANS_SULFURATION_ONE_CARBON_METABOLISM_AND_RELATED_PATHWAYS.html]

WP_GLUTATHIONE_METABOLISM: Glutathione metabolism [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_GLUTATHIONE_METABOLISM.html]

KEGG_GLUTATHIONE_METABOLISM: Glutathione metabolism [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KEGG_GLUTATHIONE_METABOLISM.html]

HOSHIDA_LIVER_CANCER_LATE_RECURRENCE_UP: Genes whose expression correlated with higher risk of late recurrence of hepatocellular carcinoma (HCC). [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/HOSHIDA_LIVER_CANCER_LATE_RECURRENCE_UP.html]

WP_NRF2_PATHWAY: NRF2 pathway [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_NRF2_PATHWAY.html]

WP_NUCLEAR_RECEPTORS_META_PATHWAY: Nuclear receptors meta pathway [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_NUCLEAR_RECEPTORS_META_PATHWAY.html]

ANDERSEN_LIVER_CANCER_KRT19_DN: Genes under-expressed in KRT19-positive [GeneID=3880] hepatocellular carcinoma. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/ANDERSEN_LIVER_CANCER_KRT19_DN.html]

HOSHIDA_LIVER_CANCER_SUBCLASS_S3: Genes from 'subtype S3' signature of hepatocellular carcinoma (HCC): hepatocyte differentiation. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/HOSHIDA_LIVER_CANCER_SUBCLASS_S3.html]

KEGG_MEDICUS_REFERENCE_GLUTATHIONE_BIOSYNTHESIS: Pathway Definition from KEGG: Cys+Glu -- (GCLC+GCLM) >> GSS -> GSH -- GPX -> GSSG [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KEGG_MEDICUS_REFERENCE_GLUTATHIONE_BIOSYNTHESIS.html]

REACTOME_ARACHIDONIC_ACID_METABOLISM: Arachidonic acid metabolism [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_ARACHIDONIC_ACID_METABOLISM.html]

KEGG_ARACHIDONIC_ACID_METABOLISM: Arachidonic acid metabolism [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KEGG_ARACHIDONIC_ACID_METABOLISM.html]

REACTOME_DETOXIFICATION_OF_REACTIVE_OXYGEN_SPECIES: Detoxification of Reactive Oxygen Species [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_DETOXIFICATION_OF_REACTIVE_OXYGEN_SPECIES.html]

REACTOME_RNA_POLYMERASE_II_TRANSCRIPTION: RNA Polymerase II Transcription [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_RNA_POLYMERASE_II_TRANSCRIPTION.html]

REACTOME_CELLULAR_RESPONSE_TO_CHEMICAL_STRESS: Cellular response to chemical stress [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_CELLULAR_RESPONSE_TO_CHEMICAL_STRESS.html]

REACTOME_TP53_REGULATES_METABOLIC_GENES: TP53 Regulates Metabolic Genes [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_TP53_REGULATES_METABOLIC_GENES.html]

WP_FOLATE_METABOLISM: Folate metabolism [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_FOLATE_METABOLISM.html]

ZHANG_ANTIVIRAL_RESPONSE_TO_RIBAVIRIN_UP: Genes up-regulated in A549 cells (lung carcinoma) upon infection with RSV (respiratory syncytial virus) and up-regulated by further treatment with ribavirin [PubChem=5064]. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/ZHANG_ANTIVIRAL_RESPONSE_TO_RIBAVIRIN_UP.html]

REACTOME_CELLULAR_RESPONSES_TO_STIMULI: Cellular responses to stimuli [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_CELLULAR_RESPONSES_TO_STIMULI.html]

REACTOME_SYNTHESIS_OF_15_EICOSATETRAENOIC_ACID_DERIVATIVES: Synthesis of 15-eicosatetraenoic acid derivatives [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_SYNTHESIS_OF_15_EICOSATETRAENOIC_ACID_DERIVATIVES.html]

REACTOME_SYNTHESIS_OF_12_EICOSATETRAENOIC_ACID_DERIVATIVES: Synthesis of 12-eicosatetraenoic acid derivatives [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_SYNTHESIS_OF_12_EICOSATETRAENOIC_ACID_DERIVATIVES.html]

REACTOME_SYNTHESIS_OF_5_EICOSATETRAENOIC_ACIDS: Synthesis of 5-eicosatetraenoic acids [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_SYNTHESIS_OF_5_EICOSATETRAENOIC_ACIDS.html]

WANG_ESOPHAGUS_CANCER_VS_NORMAL_UP: Up-regulated genes specific to esophageal adenocarcinoma (EAC) relative to normal tissue. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WANG_ESOPHAGUS_CANCER_VS_NORMAL_UP.html]

WP_SELENIUM_MICRONUTRIENT_NETWORK: Selenium micronutrient network [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_SELENIUM_MICRONUTRIENT_NETWORK.html]

PROVENZANI_METASTASIS_UP: Genes up-regulated in polysomal and total RNA samples from SW480 cells (primary colorectal carcinoma, CRC) compared to the SW620 cells (lymph node metastasis from the same individual). [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/PROVENZANI_METASTASIS_UP.html]

PID_TAP63_PATHWAY: Validated transcriptional targets of TAp63 isoforms [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/PID_TAP63_PATHWAY.html]

REACTOME_TRANSCRIPTIONAL_REGULATION_BY_TP53: Transcriptional Regulation by TP53 [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_TRANSCRIPTIONAL_REGULATION_BY_TP53.html]

RIEGE_DELTANP63_DIRECT_TARGETS_UP: Genes directly up-regulated by DeltaNp63, the p63 isoform that lacks the canonical transactivation domain and is predominantly expressed in stratifying epithelia, identified through a meta-analysis of both cell lines and primary cells. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/RIEGE_DELTANP63_DIRECT_TARGETS_UP.html]

NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_UP: Up-regulated genes in peripheral zone of human pancreatic cancer growing in the pancreas of nude mice compared to that of the tumor from the central zone. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_UP.html]

IGARASHI_ATF4_TARGETS_DN: Genes down-regulated in A549 cells (lung cancer) after knockdown of ATF4 [GeneID=468] by RNAi. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/IGARASHI_ATF4_TARGETS_DN.html]

WEIGEL_OXIDATIVE_STRESS_BY_HNE_AND_TBH: Oxidative stress genes down-regulated in ARPE-19 cells (retinal pigmented epithelium) in response to HNE and tBH [PubChem=5283344;6410]. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WEIGEL_OXIDATIVE_STRESS_BY_HNE_AND_TBH.html]

7. Gene Descriptions

NCBI Gene Summary: The protein encoded by this gene belongs to the glutathione peroxidase family, members of which catalyze the reduction of organic hydroperoxides and hydrogen peroxide (H2O2) by glutathione, and thereby protect cells against oxidative damage. Several isozymes of this gene family exist in vertebrates, which vary in cellular location and substrate specificity. This isozyme is predominantly expressed in the gastrointestinal tract (also in liver in human), is localized in the cytoplasm, and whose preferred substrate is hydrogen peroxide. Overexpression of this gene is associated with increased differentiation and proliferation in colorectal cancer. This isozyme is also a selenoprotein, containing the rare amino acid selenocysteine (Sec) at its active site. Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2016]

GeneCards Summary: GPX2 (Glutathione Peroxidase 2) is a Protein Coding gene. Diseases associated with GPX2 include Ileocolitis and Colorectal Cancer. Among its related pathways are Fatty acid metabolism and Glutathione conjugation. Gene Ontology (GO) annotations related to this gene include electron transfer activity and glutathione peroxidase activity. An important paralog of this gene is GPX1.

UniProtKB/Swiss-Prot Summary: Could play a major role in protecting mammals from the toxicity of ingested organic hydroperoxides [PMID: 8428933]. Tert-butyl hydroperoxide, cumene hydroperoxide and linoleic acid hydroperoxide but not phosphatidycholine hydroperoxide, can act as acceptors [PMID: 8428933].

8. Cellular Location of Gene Product

Cytoplasmic expression in a few tissues. Mainly localized to the cytosol. In addition localized to the cytokinetic bridge & mitotic spindle. Predicted location: Intracellular [https://www.proteinatlas.org/ENSG00000176153/subcellular]

9. Mechanistic Information

Summary

Gpx2 encodes for the glutathione peroxidase 2 enzyme, which protects cells from oxidative damage by reducing organic hydroperoxides and hydrogen peroxide using glutathione as a substrate [CS: 10]. In the liver, Gpx2 is upregulated in response to toxic insults such as hepatotoxins (bromobenzene, N-diethylnitrosamine, indole-3-carbinol, flutamide, piperonyl butoxide, MeIQx) [CS: 7], thereby enhancing the detoxification of reactive oxygen species (ROS) and hydroperoxides generated during the metabolism of these compounds [CS: 9]. This increased expression of Gpx2 leads to elevated glutathione peroxidase activity, which counteracts the oxidative stress by neutralizing the hydroperoxides, thus contributing to the survival of liver cells [CS: 9].

The upregulation of Gpx2 in the context of toxic events and diseases is mechanistically associated with the activation of transcriptional pathways sensitive to oxidative stress, such as the Nrf2 pathway [CS: 9]. Upon the liver encountering toxic compounds, ROS are generated which can lead to the oxidation of thiol groups in specific proteins, like Keap1 [CS: 8]. The modification of Keap1 releases Nrf2, allowing it to translocate to the nucleus and activate antioxidant response element-driven genes such as Gpx2 [CS: 8]. The stabilization of Gpx2 mRNA under conditions of marginal selenium deficiency ensures continued detoxification capacity against organic hydroperoxides even when selenium, a co-factor for the active site of Gpx2, is limited [CS: 7].

10. Upstream Regulators

11. Tissues/Cell Type Where Genes are Overexpressed

Tissue type enchanced: gallbladder, intestine, liver, stomach, urinary bladder (tissue enhanced) [https://www.proteinatlas.org/ENSG00000176153/tissue]

Cell type enchanced: cholangiocytes, distal enterocytes, gastric mucus-secreting cells, hepatocytes, paneth cells, squamous epithelial cells, undifferentiated cells (cell type enhanced) [https://www.proteinatlas.org/ENSG00000176153/single+cell+type]

12. Role of Gene in Other Tissues

13. Chemicals Known to Elicit Transcriptional Response of Biomarker in Tissue of Interest

Compounds that increase expression of the gene:

Compounds that decrease expression of the gene:

14. DisGeNet Biomarker Associations to Disease in Organ of Interest

Most relevant biomarkers with lower score or lower probability of association with disease or organ of interest: