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Induction of glutathione peroxidase 4 expression during enterocytic cell differentiation.

ABSTRACT: Glutathione peroxidase 4 (GPx4), an abundant selenoenzyme, is ubiquitously expressed in a tissue-, cell- and differentiation-dependent manner, and it is localized in cytoplasmic, mitochondrial, and nuclear cellular compartments. Here, we report cytoplasmic and nuclear localization of GPx4 in Caco-2 intestinal epithelial cells. Enterocytic differentiation of Caco-2 cells triggers an increase in GPx4 mRNA and protein levels, mediated by enhanced promoter activity. We identified a combined cAMP response element (CREB) and CCAAT/enhancer binding protein (C/EBP) site as critical for the differentiation-triggered GPx4 promoter activity. Induction of GPx4 correlated with C/EBP? transcript levels during differentiation, suggesting a role of C/EBP? as regulator of enterocytic GPx4 expression. Consistent with the in vitro results, GPx4 protein was detected in cytoplasmic and nuclear compartments of enterocytes in human intestinal epithelia. GPx4 is uniformly expressed in colonic crypts and is differentially expressed along the crypt-to-villus axis in the small intestine with a more pronounced expression of GPx4 in the upper villi, which contain fully differentiated enterocytes. These data suggest that intestinal GPx4 expression is modulated by the enterocytic differentiation program, and the results support a direct role of nuclear GPx4 in the (selenium-dependent) prevention of oxidative damage in the gastrointestinal tract.

SUBMITTER: Speckmann B

PROVIDER: S-EPMC3060527 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Induction of glutathione peroxidase 4 expression during enterocytic cell differentiation.

Speckmann Bodo B Bidmon Hans-Jürgen HJ Pinto Antonio A Anlauf Martin M Sies Helmut H Steinbrenner Holger H

The Journal of biological chemistry 20110120 12

Glutathione peroxidase 4 (GPx4), an abundant selenoenzyme, is ubiquitously expressed in a tissue-, cell- and differentiation-dependent manner, and it is localized in cytoplasmic, mitochondrial, and nuclear cellular compartments. Here, we report cytoplasmic and nuclear localization of GPx4 in Caco-2 intestinal epithelial cells. Enterocytic differentiation of Caco-2 cells triggers an increase in GPx4 mRNA and protein levels, mediated by enhanced promoter activity. We identified a combined cAMP res ...[more]

PMID: 21252226

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Project description:BackgroundGlutathione (GSH) is one of the most important agents of the antioxidant defense system of the cell because, in conjunction with the enzymes glutathione peroxidase (GSH-Px) and glutathione S transferase pi (GSTpi), it plays a central role in the detoxification and biotransformation of chemotherapeutic drugs. This study evaluated the expression of GSH and the GSH-Px and GSTpi enzymes by immunohistochemistry in 30 canine mammary tumors, relating the clinicopathological parameters, clinical outcome and survival of the bitches. In an in vitro study, the expression of the genes glutamate cysteine ligase (GCLC) and glutathione synthetase (GSS) that synthesize GSH and GSH-Px gene were verified by qPCR and subjected to treatment with doxorubicin, to check the resistance of cancer cells to chemotherapy.ResultsThe immunohistochemical expression of GSH, GSH-Px and GSTpi was compared with the clinical and pathological characteristics and the clinical outcome in the bitches, including metastasis and death.The results showed that high immunoexpression of GSH was correlated to the absence of tumor ulceration and was present in dogs without metastasis (P < 0.05). There was significant correlation of survival with the increase of GSH (P < 0.05). The expression of the GSH-Px and GSTpi enzymes showed no statistically significant correlation with the analyzed variables (p > 0.05). The analysis of the relative expression of genes responsible for the synthesis of GSH (GCLC and GSS) and GSH-Px by quantitative PCR was done with cultured cells of 10 tumor fragments from dogs with mammary tumors.The culture cells showed a decrease in GCLC and GSS expression when compared with no treated cells (P < 0.05). High GSH immunoexpression was associated with better clinical outcomes.ConclusionTherefore, high expression of the GSH seems to play an important role in the clinical outcome of patients with mammary tumors and suggest its use as prognostic marker. The in vitro doxorubicin treatment significantly reduces the expression of GCLC and GSS genes so we can consider them to be candidates for predictive markers of therapeutic response in mammary cancer.

Project description:BackgroundEndoplasmic reticulum (ER) calcium storage and release play important roles in B lymphocyte maturation, survival, antigen-dependent cell activation and immunoglobulin synthesis. Calcium is accumulated in the endoplasmic reticulum (ER) by Sarco/Endoplasmic Reticulum Calcium ATPases (SERCA enzymes). Because lymphocyte function is critically dependent on SERCA activity, it is important to understand qualitative and quantitative changes of SERCA protein expression that occur during B lymphoid differentiation and leukemogenesis.MethodsIn this work we investigated the modulation of SERCA expression during the pharmacologically induced differentiation of leukemic precursor B lymphoblast cell lines that carry the E2A-PBX1 fusion oncoprotein. Changes of SERCA levels during differentiation were determined and compared to those of established early B lymphoid differentiation markers. SERCA expression of the cells was compared to that of mature B cell lines as well, and the effect of the direct inhibition of SERCA-dependent calcium transport on the differentiation process was investigated.ResultsWe show that E2A-PBX1+ leukemia cells simultaneously express SERCA2 and SERCA3-type calcium pumps; however, their SERCA3 expression is markedly inferior to that of mature B cells. Activation of protein kinase C enzymes by phorbol ester leads to phenotypic differentiation of the cells, and this is accompanied by the induction of SERCA3 expression. Direct pharmacological inhibition of SERCA-dependent calcium transport during phorbol ester treatment interferes with the differentiation process.ConclusionThese data show that the calcium pump composition of the ER is concurrent with increased SERCA3 expression during the differentiation of precursor B acute lymphoblastic leukemia cells, that a cross-talk exists between SERCA function and the control of differentiation, and that SERCA3 may constitute an interesting new marker for the study of early B cell phenotype.

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Induction of glutathione peroxidase 4 expression during enterocytic cell differentiation.

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Induction of glutathione peroxidase 4 expression during enterocytic cell differentiation.

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