title: EPO modulation of cell-cycle regulatory genes, and cell division, in primary bone marrow erythroblasts.
abstract: Erythropoietin (EPO's) actions on erythroblasts are ascribed largely to survival effects. Certain studies, however, point to EPO-regulated proliferation. To investigate this problem in a primary system, Kit(pos)CD71(high) erythroblasts were prepared from murine bone marrow, and were first used in the array-based discovery of EPO-modulated cell-cycle regulators. Five cell-cycle progression factors were rapidly up-modulated: nuclear protein 1 (Nupr1), G1 to S phase transition 1 (Gspt1), early growth response 1 (Egr1), Ngfi-A binding protein 2 (Nab2), and cyclin D2. In contrast, inhibitory cyclin G2, p27/Cdkn1b, and B-cell leukemia/lymphoma 6 (Bcl6) were sharply down-modulated. For CYCLIN G2, ectopic expression also proved to selectively attenuate EPO-dependent UT7epo cell-cycle progression at S-phase. As analyzed in primary erythroblasts expressing minimal EPO receptor alleles, EPO repression of cyclin G2 and Bcl6, and induction of cyclin D2, were determined to depend on PY343 (and Stat5) signals. Furthermore, erythroblasts expressing a on PY-null EPOR-HM allele were abnormally distributed in G0/G1. During differentiation divisions, EPOR-HM Ter119(pos) erythroblasts conversely accumulated in S-phase and faltered in an apparent EPO-directed transition to G0/G1. EPO/EPOR signals therefore control the expression of select cell-cycle regulatory genes that are proposed to modulate stage-specific decisions for erythroblast cell-cycle progression.
authors.affiliation: Program in Stem and Progenitor Cell Biology, Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
authors.forename: Madhu
authors.initials: M
authors.lastname: Menon
authors.forename: William
authors.initials: W
authors.lastname: Kapelle
authors.forename: Olga
authors.initials: O
authors.lastname: Bogacheva
authors.forename: Oleg
authors.initials: O
authors.lastname: Bogachev
authors.forename: Estelle
authors.initials: E
authors.lastname: Houde
authors.forename: Sarah
authors.initials: S
authors.lastname: Browne
authors.forename: Pradeep
authors.initials: P
authors.lastname: Sathyanarayana
authors.forename: Don M
authors.initials: DM
authors.lastname: Wojchowski
mesh_terms: D000483:Alleles; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division; D002478:Cells, Cultured; D004900:Erythroblasts / Q000166:cytology* / Q000378:metabolism*; D004921:Erythropoietin / Q000494:pharmacology*; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D017467:Receptors, Erythropoietin; D004921:Erythropoietin