Functions of GI‐GPx: Lessons from selenium‐dependent expression and intracellular localization

Brigelius‐Flohé, Regina; Müller, Cordula; Menard, Julien A.; Florian, Simone; Schmehl, K.; Wingler, Kirstin

doi:10.1002/biof.5520140114

Cited by 57 publications

(38 citation statements)

References 17 publications

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“…(i) GI-GPx mRNA is extremely stable in selenium deficiency, which ranks GI-GPx high in the hierarchy of selenoproteins and, thus, points to more vital functions than those the low-ranking selenoproteins such as cGPx may have (45,65). (ii) In accordance with the high mRNA stability, GI-GPx protein is synthesized first upon selenium resupplementation, while cGPx follows with a delay of at least 24 h, as has been demonstrated in vitro and in vivo (10,66). (iii) Unlike cGPx, GI-GPx is not uniformly expressed along the crypt-tovillus axis but is preferentially located in the crypts (22).…”

mentioning

confidence: 72%

The GI-GPx Gene Is a Target for Nrf2

Banning

Deubel

Kluth

et al. 2005

Molecular and Cellular Biology

302

115

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The gastrointestinal glutathione peroxidase (GI-GPx, GPx2) is a selenoprotein that was suggested to act as barrier against hydroperoxide absorption but has also been implicated in the control of inflammation and malignant growth. In CaCo-2 cells, GI-GPx was induced by t-butyl hydroquinone (tBHQ) and sulforaphane (SFN), i.e., "antioxidants" known to activate the "antioxidant response element" (ARE) via electrophilic thiol modification of Keap1 in the Nrf2/Keap1 system. The functional significance of a putative ARE in the GI-GPx promoter was validated by transcriptional activation of reporter gene constructs upon exposure to electrophiles (tBHQ, SFN, and curcumin) or overexpression of Nrf2 and by reversal of these effects by mutation of the ARE in the promoter and by overexpressed Keap1. Binding of Nrf2 to the ARE sequence in authentic gpx2 was corroborated by chromatin immunoprecipitation. Thus, the presumed natural antioxidants sulforaphane and curcumin may exert their anti-inflammatory and anticarcinogenic effects not only by induction of phase 2 enzymes but also by the up-regulation of the selenoprotein GI-GPx.

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mentioning

confidence: 72%

The GI-GPx Gene Is a Target for Nrf2

Banning

Deubel

Kluth

et al. 2005

Molecular and Cellular Biology

302

115

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“…The role played by this enzyme in cancer remains obscure, but a recent study suggested an association between GST M4 polymorphisms and lung cancer risk, implying that the activity of this enzyme might be involved in tumour development [23]. GSH peroxidase 2 mRNA was also found to be more frequently expressed in tumour as compared to normal breast tissue; this enzyme can protect cells from free radicals and also regulate proliferation and apoptosis through redox signalling [24] and thus its increased expression may confer a survival advantage to tumour cells. Expression of GSH peroxidase 2 has been established in breast tissue [25] and increased expression of this enzyme has recently been reported in lung adenocarcinomas and in normal alveolar epithelium from smokers as compared to normal lung tissue from non-smokers [26].…”

Section: Discussionmentioning

confidence: 99%

Drug metabolism-related genes as potential biomarkers: analysis of expression in normal and tumour breast tissue

Martínez

Kennedy

Doolan

et al. 2007

Breast Cancer Res Treat

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The complex role of drug metabolism-related enzymes and their possible influence in cancer development, treatment and outcome has not yet been completely elucidated. There is evidence that these enzymes can activate certain environmental procarcinogens to more toxic derivatives and thus a role has been proposed for them in carcinogenesis. The fact that they can also inactivate a number of chemotherapeutic drugs has raised the possibility of these enzymes influencing the sensitivity of tumour cells to anticancer agents. In this report, we analyse the expression of drug metabolism-related genes within a whole genome microarray study of 104 breast cancer and 17 normal breast specimens. Kaplan-Meier survival curves, Chi-squared, and Cox Regression analyses were used to identify associations between expression of gene transcripts and patients' clinicopathological and survival data. Our results show that several of these genes are significantly expressed in both normal and tumour tissue; in many cases, expression is altered in the tumour specimens as compared to normal breast tissue. Moreover, expression of ARNT2 and GST A1 was correlated with prognosis. Kaplan-Meier analysis showed expression of ARNT2 mRNA to correlate significantly with favourable disease outcome for patients, in terms of both their disease-free survival (P = 0.0094) and overall survival (P = 0.0018) times from diagnosis, while detection of GST A1 mRNA correlated with shortened disease-free survival (P = 0.0131) and overall survival (P = 0.0028). Multivariate analysis indicated GST A1 expression to be an independent prognostic factor for overall survival (P = 0.045). Our results suggest a possible use of ARNT2 and GST A1 as prognostic breast cancer biomarkers.

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“…Interestingly, the gastrointestinal tract expresses all four common GPX (GPX1-GPX4), which may suggest a significant role in colonic function (e.g., as a barrier for reactive oxygen species; refs. 26,31,32). Support for the importance of these selenoenzymes comes from an animal study showing that targeted disruption of both cytosolic and gastrointestinal GPX (GPX1 and GPX2, respectively) genes results in accumulation of lipid hydroperoxides (33) and high susceptibility to inflammation and colon cancer in mice (25,34).…”

Section: Introductionmentioning

confidence: 99%

Variation in the Selenoenzyme Genes and Risk of Advanced Distal Colorectal Adenoma

Peters

Chatterjee

Hayes

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

105

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Background: Epidemiologic and animal studies provide evidence for a chemopreventive effect of selenium on colorectal cancer, which may be mediated by the antioxidative and anti-inflammatory properties of selenoenzymes. We therefore investigated whether genetic variants in selenoenzymes abundantly expressed in the colon are associated with advanced colorectal adenoma, a cancer precursor. Methods: Cases with a left-sided advanced adenoma (n = 772) and matched controls (n = 777) screen negative for polyps based on sigmoidoscopy examination were randomly selected from participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The underlying genetic variation was determined by resequencing. We genotyped 44 tagging single nucleotide polymorphisms (SNP) in six genes [glutathione peroxidase 1-4 (GPX1, GPX2, GPX3, and GPX4), selenoprotein P (SEPP1), and thioredoxin reductase 1 (TXNRD1)] to efficiently predict common variation across these genes. Results: Four variants in SEPP1 were significantly associated with advanced adenoma risk. A rare variant in the 5 ¶ region of SEPP1 (-4166C>G) was present in nine cases but in none of the controls (exact P = 0.002). Three SNPs located in the 3 ¶ region of SEPP1, which

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Functions of GI‐GPx: Lessons from selenium‐dependent expression and intracellular localization

Cited by 57 publications

References 17 publications

The GI-GPx Gene Is a Target for Nrf2

The GI-GPx Gene Is a Target for Nrf2

Drug metabolism-related genes as potential biomarkers: analysis of expression in normal and tumour breast tissue

Variation in the Selenoenzyme Genes and Risk of Advanced Distal Colorectal Adenoma

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