In vivo regulation of erythropoiesis by chemically inducible dimerization of the erythropoietin receptor intracellular domain

Erythropoietin (Epo) and its receptor (EpoR) are required for the regulation of erythropoiesis. Epo binds to the EpoR homodimer on the surface of erythroid progenitors and erythroblasts, and positions the intracellular domains of the homodimer to be in close proximity with each other. This conformat...

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Published in:PloS one 2015-03, Vol.10 (3), p.e0119442-e0119442
Main Authors: Suzuki, Norio, Mukai, Harumi Y, Yamamoto, Masayuki
Format: Article
Language:English
Subjects:
Amino acid sequence
Amino Acid Sequence - genetics
Amino acids
Anemia
Anemia - drug therapy
Anemia - genetics
Animals
Biochemistry
Cellular signal transduction
Cytokines
Dimerization
Erythroblasts
Erythropoiesis
Erythropoiesis - drug effects
Erythropoiesis - genetics
Erythropoietin
Erythropoietin - biosynthesis
Erythropoietin - genetics
GATA-1 protein
GATA1 Transcription Factor - genetics
Gene expression
Gene Expression Regulation, Developmental - drug effects
Genetic engineering
Glycoproteins
Hemopoiesis
Intracellular
Intracellular signalling
Kinases
Laboratory animals
Medicine
Mice
Mice, Transgenic
Oral administration
Protein Multimerization - drug effects
Protein Structure, Tertiary
Proteins
Receptors, Erythropoietin - biosynthesis
Receptors, Erythropoietin - genetics
Rodents
Signal transduction
Signal Transduction - drug effects
Signal Transduction - genetics
Studies
Tacrolimus - administration & dosage
Tacrolimus - analogs & derivatives
Transgenic animals
Transgenic mice
University graduates
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creator Suzuki, Norio
Mukai, Harumi Y
Yamamoto, Masayuki
description Erythropoietin (Epo) and its receptor (EpoR) are required for the regulation of erythropoiesis. Epo binds to the EpoR homodimer on the surface of erythroid progenitors and erythroblasts, and positions the intracellular domains of the homodimer to be in close proximity with each other. This conformational change is sufficient for the initiation of Epo-EpoR signal transduction. Here, we established a system of chemically regulated erythropoiesis in transgenic mice expressing a modified EpoR intracellular domain (amino acids 247-406) in which dimerization is induced using a specific compound (chemical inducer of dimerization, CID). Erythropoiesis is reversibly induced by oral administration of the CID to the transgenic mice. Because transgene expression is limited to hematopoietic cells by the Gata1 gene regulatory region, the effect of the CID is limited to erythropoiesis without adverse effects. Additionally, we show that the 160 amino acid sequence is the minimal essential domain of EpoR for intracellular signaling of chemically inducible erythropoiesis in vivo. We propose that the CID-dependent dimerization system combined with the EpoR intracellular domain and the Gata1 gene regulatory region generates a novel peroral strategy for the treatment of anemia.
doi_str_mv 10.1371/journal.pone.0119442
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Epo binds to the EpoR homodimer on the surface of erythroid progenitors and erythroblasts, and positions the intracellular domains of the homodimer to be in close proximity with each other. This conformational change is sufficient for the initiation of Epo-EpoR signal transduction. Here, we established a system of chemically regulated erythropoiesis in transgenic mice expressing a modified EpoR intracellular domain (amino acids 247-406) in which dimerization is induced using a specific compound (chemical inducer of dimerization, CID). Erythropoiesis is reversibly induced by oral administration of the CID to the transgenic mice. Because transgene expression is limited to hematopoietic cells by the Gata1 gene regulatory region, the effect of the CID is limited to erythropoiesis without adverse effects. Additionally, we show that the 160 amino acid sequence is the minimal essential domain of EpoR for intracellular signaling of chemically inducible erythropoiesis in vivo. We propose that the CID-dependent dimerization system combined with the EpoR intracellular domain and the Gata1 gene regulatory region generates a novel peroral strategy for the treatment of anemia.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25790231</pmid><doi>10.1371/journal.pone.0119442</doi><oa>free_for_read</oa></addata></record>
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1932-6203
language eng
recordid cdi_plos_journals_1664782743
source Publicly Available Content Database; PubMed Central
subjects Amino acid sequence
Amino Acid Sequence - genetics
Amino acids
Anemia
Anemia - drug therapy
Anemia - genetics
Animals
Biochemistry
Cellular signal transduction
Cytokines
Dimerization
Erythroblasts
Erythropoiesis
Erythropoiesis - drug effects
Erythropoiesis - genetics
Erythropoietin
Erythropoietin - biosynthesis
Erythropoietin - genetics
GATA-1 protein
GATA1 Transcription Factor - genetics
Gene expression
Gene Expression Regulation, Developmental - drug effects
Genetic engineering
Glycoproteins
Hemopoiesis
Intracellular
Intracellular signalling
Kinases
Laboratory animals
Medicine
Mice
Mice, Transgenic
Oral administration
Protein Multimerization - drug effects
Protein Structure, Tertiary
Proteins
Receptors, Erythropoietin - biosynthesis
Receptors, Erythropoietin - genetics
Rodents
Signal transduction
Signal Transduction - drug effects
Signal Transduction - genetics
Studies
Tacrolimus - administration & dosage
Tacrolimus - analogs & derivatives
Transgenic animals
Transgenic mice
University graduates
title In vivo regulation of erythropoiesis by chemically inducible dimerization of the erythropoietin receptor intracellular domain
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