title: A novel mechanism of cooperation between c-Kit and erythropoietin receptor. Stem cell factor induces the expression of Stat5 and erythropoietin receptor, resulting in efficient proliferation and survival by erythropoietin.
abstract: Optimal production of red cells in vivo requires collaboration between c-Kit, erythropoietin receptor (Epo-R), and GATA-1. However, the mechanism(s) of collaboration remain unclear. Utilizing an embryonic stem cell-derived erythroid progenitor cell line from mice deficient in GATA-1, we have examined the role of c-Kit and Epo-R in erythroid cell proliferation, survival, and differentiation. In the absence of GATA-1, we demonstrate an essential role for c-Kit in survival and proliferation of erythroid progenitors via the regulation of Bcl-2 expression. In addition, we demonstrate that Epo-R and Stat5 are regulated by a second, novel mechanism. We demonstrate that c-Kit stimulation by stem cell factor is essential for the maintenance of Epo-R and Stat5 protein expression, which results in significantly enhanced Bcl-x(L) induction and survival of erythroid progenitors in response to Epo stimulation. Restoration of GATA-1 function results in terminal erythroid maturation and up-regulation of Epo-R and Bcl-x(L) expression, leading also to significantly enhanced survival of terminally differentiating erythroid progenitors in the presence of only Epo. These results demonstrate that c-Kit and Epo-R have unique role(s) during distinct phases of erythroid maturation, and both stem cell factor and Epo contribute to the regulation of the Epo-R-Stat5-Bcl-x(L) pathway to ensure optimal survival, proliferation, and differentiation of erythroid progenitors.
authors.affiliation: Herman B Wells Center for Pediatric Research, Department of Pediatrics, James Whitcomb Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. rkapur@iupui.edu
authors.forename: R
authors.initials: R
authors.lastname: Kapur
authors.forename: L
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D050981:Erythroid-Specific DNA-Binding Factors; D004921:Erythropoietin / Q000494:pharmacology*; D050982:GATA1 Transcription Factor; D005786:Gene Expression Regulation / Q000187:drug effects; D008894:Milk Proteins; D008954:Models, Biological; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D012097:Repressor Proteins / Q000378:metabolism; D050799:STAT5 Transcription Factor; D019089:Stem Cell Factor / Q000494:pharmacology*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D051020:bcl-X Protein
chemical_list: C494813:Bcl2l1 protein, rat; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494690:Gata1 protein, rat; D008894:Milk Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D019089:Stem Cell Factor; D015534:Trans-Activators; D014157:Transcription Factors; D051020:bcl-X Protein; D004921:Erythropoietin; D019009:Proto-Oncogene Proteins c-kit