title: The expression and activity of thioredoxin reductase 1 splice variants v1 and v2 regulate the expression of genes associated with differentiation and adhesion.
abstract: The mammalian redox-active selenoprotein thioredoxin reductase (TrxR1) is a main player in redox homoeostasis. It transfers electrons from NADPH to a large variety of substrates, particularly to those containing redox-active cysteines. Previously, we reported that the classical form of cytosolic TrxR1 (TXNRD1_v1), when overexpressed in human embryonic kidney cells (HEK-293), prompted the cells to undergo differentiation [Nalvarte et al. (2004) J. Biol. Chem. 279: , 54510-54517]. In the present study, we show that several genes associated with differentiation and adhesion are differentially expressed in HEK-293 cells stably overexpressing TXNRD1_v1 compared with cells expressing its splice variant TXNRD1_v2. Overexpression of these two splice forms resulted in distinctive effects on various aspects of cellular functions including gene regulation patterns, alteration of growth rate, migration and morphology and susceptibility to selenium-induced toxicity. Furthermore, differentiation of the neuroblastoma cell line SH-SY5Y induced by all-trans retinoic acid (ATRA) increased both TXNRD1_v1 and TXNRD1_v2 expressions along with several of the identified genes associated with differentiation and adhesion. Selenium supplementation in the SH-SY5Y cells also induced a differentiated morphology and changed expression of the adhesion protein fibronectin 1 and the differentiation marker cadherin 11, as well as different temporal expression of the studied TXNRD1 variants. These data suggest that both TXNRD1_v1 and TXNRD1_v2 have distinct roles in differentiation, possibly by altering the expression of the genes associated with differentiation, and further emphasize the importance in distinguishing each unique action of different TrxR1 splice forms, especially when studying the gene silencing or knockout of TrxR1.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institute, SE-141 83 Huddinge, Sweden ivan.nalvarte@ki.se.
authors.forename: Ivan
authors.initials: I
authors.lastname: Nalvarte
authors.affiliation: Department of Clinical Neurosciences, Karolinska Institute, SE-171 76 Stockholm, Sweden.
authors.forename: Anastasios E
authors.initials: AE
authors.lastname: Damdimopoulos
authors.affiliation: Department of Clinical Neurosciences, Karolinska Institute, SE-171 76 Stockholm, Sweden Swedish Toxicology Science Research Center (Swetox), SE-151 36, Södertälje, Sweden.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Rüegg
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine, Linköping University, SE-581 85 Linköping, Sweden.
authors.forename: Giannis
authors.initials: G
authors.lastname: Spyrou
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006801:Humans; D010084:Oxidation-Reduction; D020033:Protein Isoforms / Q000096:biosynthesis* / Q000235:genetics; D054481:Thioredoxin Reductase 1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D020033:Protein Isoforms; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1
keywords: differentiation; migration; oxidative stress; selenium; thioredoxin reductase