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T-cell Acute Leukemia 1 (TAL1) Regulation of Erythropoietin Receptor and Association with Excessive Erythrocytosis
- Source :
- The Journal of biological chemistry, vol 287, iss 44
- Publication Year :
- 2012
- Publisher :
- Elsevier BV, 2012.
-
Abstract
- During erythropoiesis, erythropoietin stimulates induction of erythroid transcription factors that activate expression of erythroid genes including the erythropoietin receptor (EPO-R) that results in increased sensitivity to erythropoietin. DNA binding of the basic helix-loop-helix transcription factor, TAL1/SCL, is required for normal erythropoiesis. A link between elevated TAL1 and excessive erythrocytosis is suggested by erythroid progenitor cells from a patient that exhibits unusually high sensitivity to erythropoietin with concomitantly elevated TAL1 and EPO-R expression. We found that TAL1 regulates EPO-R expression mediated via three conserved E-box binding motifs (CAGCTG) in the EPO-R 5' untranslated transcribed region. TAL1 increases association of the GATA-1·TAL1·LMO2·LDB1 transcription activation complex to the region that includes the transcription start site and the 5' GATA and 3' E-box motifs flanking the EPO-R transcription start site suggesting that TAL1 promotes accessibility of this region. Nucleosome shifting has been demonstrated to facilitate TAL1 but not GATA-1 binding to regulate target gene expression. Accordingly, we observed that with induced expression of EPO-R in hemotopoietic progenitor cells, nucleosome phasing shifts to increase the linker region containing the EPO-R transcription start site and TAL1 binds to the flanking 5' GATA and 3' E-box regions of the promoter. These data suggest that TAL1 binds to the EPO-R promoter to activate EPO-R expression and provides a potential link to elevated EPO-R expression leading to hypersensitivity to erythropoietin and the resultant excessive erythrocytosis.
- Subjects :
- Renilla
Male
DNA Mutational Analysis
Gene Expression
beta-Globins
Medical and Health Sciences
Biochemistry
Genes, Reporter
hemic and lymphatic diseases
Receptors
Basic Helix-Loop-Helix Transcription Factors
Receptors, Erythropoietin
GATA1 Transcription Factor
Luciferases
Promoter Regions, Genetic
Cells, Cultured
T-Cell Acute Lymphocytic Leukemia Protein 1
Regulation of gene expression
Cultured
GATA2
Molecular Bases of Disease
Cell Differentiation
Hematology
Biological Sciences
CD
GATA2 Transcription Factor
Erythropoiesis
Protein Binding
medicine.drug
Adult
Biochemistry & Molecular Biology
Cells
Kruppel-Like Transcription Factors
Mutation, Missense
Polycythemia
Biology
Promoter Regions
Genetic
Erythroid Cells
Antigens, CD
Proto-Oncogene Proteins
Genetics
medicine
Humans
Antigens
Reporter
Erythropoietin
Molecular Biology
Transcription factor
Cell Proliferation
Luciferases, Renilla
Binding Sites
Cell Biology
Janus Kinase 2
Hematopoietic Stem Cells
Molecular biology
Erythropoietin receptor
Genes
Gene Expression Regulation
Case-Control Studies
Mutation
Chemical Sciences
GATA transcription factor
Missense
TAL1
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 287
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....c9180de4f4d6f2359e157f88c743bc78