title: Cooperative signaling between cytokine receptors and the glucocorticoid receptor in the expansion of erythroid progenitors: molecular analysis by expression profiling.
abstract: Erythroid progenitors undergo renewal (proliferation without apparent differentiation) in response to erythropoietin (Epo), stem cell factor (SCF), and glucocorticoids (dexamethasone) (Dex). SCF and Dex cooperate with Epo to promote proliferation and inhibit differentiation of erythroid progenitors, while Epo alone is required to protect erythroid cells from apoptosis during terminal red cell maturation. To examine the mechanism of the synergistic interactions of Epo, SCF, and Dex, we analyzed gene expression patterns using DNA chip-based large-scale comparative gene profiling using microarrays enriched in hematopoietic transcripts or containing randomly selected genes. Differentially regulated genes were validated by real-time reverse transcription-polymerase chain reaction (RT-PCR). The results reveal cooperative regulation of gene expression by glucocorticoids and Epo/SCF on a number of genes, such as CIS, BTG1, VDUP1, CXCR4, GILZ, and RIKEN29300106B05. While Epo and SCF never showed opposite effects on gene expression, Dex either enhanced or attenuated the effect of Epo and/or SCF. Several glucocorticoid receptor (GR)-target genes were regulated by Dex only in the presence of Epo and/or SCF, suggesting that the GR functions in the context of a larger transactivation complex to regulate these genes. The data also suggest that modulation of cytokine-induced signals by the GR is an important mechanism in erythroid progenitor renewal.
authors.affiliation: Research Institute of Molecular Pathology (IMP), Dr Bohr Gasse 7, 1030 Vienna, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kolbus
authors.forename: Montserrat
authors.initials: M
authors.lastname: Blázquez-Domingo
authors.forename: Sebastian
authors.initials: S
authors.lastname: Carotta
authors.forename: Walbert
authors.initials: W
authors.lastname: Bakker
authors.forename: Susanna
authors.initials: S
authors.lastname: Luedemann
authors.forename: Marieke
authors.initials: M
authors.lastname: von Lindern
authors.forename: Peter
authors.initials: P
authors.lastname: Steinlein
authors.forename: Hartmut
authors.initials: H
authors.lastname: Beug
mesh_terms: D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D015672:Erythroid Precursor Cells / Q000166:cytology*; D004921:Erythropoietin / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008817:Mice, Mutant Strains; D020411:Oligonucleotide Array Sequence Analysis; D020239:Receptor Cross-Talk; D018121:Receptors, Cytokine / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000494:pharmacology
chemical_list: D018121:Receptors, Cytokine; D011965:Receptors, Glucocorticoid; D019089:Stem Cell Factor; D004921:Erythropoietin; D003907:Dexamethasone