title: Thioredoxin-interacting protein regulates the differentiation of murine erythroid precursors.
abstract: Thioredoxin-interacting protein (TXNIP) is involved in various cellular processes including redox control, metabolism, differentiation, growth, and apoptosis. With respect to hematopoiesis, TXNIP has been shown to play roles in natural killer cells, dendritic cells, and hematopoietic stem cells. Our study investigates the role of TXNIP in erythropoiesis. We observed a rapid and significant increase of TXNIP transcript and protein levels in mouse erythroleukemia cells treated with dimethyl sulfoxide or hexamethylene bisacetamide, inducers of erythroid differentiation. The upregulation of TXNIP was not abrogated by addition of the antioxidant N-acetylcysteine. The increase of TXNIP expression was confirmed in another model of erythroid differentiation, G1E-ER cells, which undergo differentiation upon activation of the GATA1 transcription factor. In addition, we showed that TXNIP levels are induced following inhibition of p38 or c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases. We also observed an increase in iron uptake and a decrease in transferrin receptor protein upon TXNIP overexpression, suggesting a role in iron homeostasis. In vivo, flow cytometry analysis of cells from Txnip(-/-) mice revealed a new phenotype of impaired terminal erythropoiesis in the spleen, characterized by a partial block between basophilic and late basophilic/polychromatic erythroblasts. Based on our data, TXNIP emerges as a novel regulator of terminal erythroid differentiation.
authors.affiliation: Lady Davis Institute for Medical Research, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Jadwiga J
authors.initials: JJ
authors.lastname: Gasiorek
authors.affiliation: Lady Davis Institute for Medical Research, Montreal, Quebec, Canada; Department of Physiology, McGill University, Montreal, Quebec, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Mikhael
authors.affiliation: Lady Davis Institute for Medical Research, Montreal, Quebec, Canada; Department of Physiology, McGill University, Montreal, Quebec, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Garcia-Santos
authors.affiliation: Division of Cardiology, Department of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Simon T
authors.initials: ST
authors.lastname: Hui
authors.affiliation: Lady Davis Institute for Medical Research, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada; Department of Physiology, McGill University, Montreal, Quebec, Canada.
authors.forename: Prem
authors.initials: P
authors.lastname: Ponka
authors.affiliation: Lady Davis Institute for Medical Research, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada; Department of Physiology, McGill University, Montreal, Quebec, Canada. Electronic address: volker.blank@mcgill.ca.
authors.forename: Volker
authors.initials: V
authors.lastname: Blank
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D004900:Erythroblasts / Q000378:metabolism*; D004920:Erythropoiesis / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006418:Heme / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D007501:Iron / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009570:Nitriles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013879:Thioredoxins / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000873:Anthracenes; D002070:Butadienes; D002352:Carrier Proteins; D007093:Imidazoles; D009570:Nitriles; D011725:Pyridines; C445672:Txnip protein, mouse; C113580:U 0126; C432165:pyrazolanthrone; D006418:Heme; D013879:Thioredoxins; D007501:Iron; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole