title: The glucocorticoid receptor is a key regulator of the decision between self-renewal and differentiation in erythroid progenitors.
abstract: During development and in regenerating tissues such as the bone marrow, progenitor cells constantly need to make decisions between proliferation and differentiation. We have used a model system, normal erythroid progenitors of the chicken, to determine the molecular players involved in making this decision. The molecules identified comprised receptor tyrosine kinases (c-Kit and c-ErbB) and members of the nuclear hormone receptor superfamily (thyroid hormone receptor and estrogen receptor). Here we identify the glucocorticoid receptor (GR) as a key regulator of erythroid progenitor self-renewal (i.e. continuous proliferation in the absence of differentiation). In media lacking a GR ligand or containing a GR antagonist, erythroid progenitors failed to self-renew, even if c-Kit, c-ErbB and the estrogen receptor were activated simultaneously. To induce self-renewal, the GR required the continuous presence of an activated receptor tyrosine kinase and had to cooperate with the estrogen receptor for full activity. Mutant analysis showed that DNA binding and a functional AF-2 transactivation domain are required for proliferation stimulation and differentiation arrest. c-myb was identified as a potential target gene of the GR in erythroblasts. It could be demonstrated that delta c-Myb, an activated c-Myb protein, can functionally replace the GR.
authors.affiliation: Institute of Molecular Pathology, Vienna, Austria.
authors.forename: O
authors.initials: O
authors.lastname: Wessely
authors.forename: E M
authors.initials: EM
authors.lastname: Deiner
authors.forename: H
authors.initials: H
authors.lastname: Beug
authors.forename: M
authors.initials: M
authors.lastname: von Lindern
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D002454:Cell Differentiation; D002455:Cell Division; D002642:Chick Embryo; D002645:Chickens; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000502:physiology; D003907:Dexamethasone / Q000378:metabolism; D066246:ErbB Receptors / Q000502:physiology; D015672:Erythroid Precursor Cells / Q000166:cytology*; D005668:Furylfuramide / Q000378:metabolism; D007700:Kinetics; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000502:physiology; D020598:Proto-Oncogene Proteins c-myb; D011960:Receptors, Estrogen / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D019089:Stem Cell Factor / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D019089:Stem Cell Factor; D015534:Trans-Activators; D005668:Furylfuramide; D003907:Dexamethasone; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases