title: Erythropoietin down-regulates stem cell factor receptor (Kit) expression in the leukemic proerythroblast: role of Lyn kinase.
abstract: Overexpression of the transcription factor Spi-1/PU.1 by transgenesis in mice induces a maturation arrest at the proerythroblastic stage of differentiation. We have previously isolated a panel of spi-1 transgenic erythroleukemic cell lines that proliferated in the presence of either erythropoietin (Epo) or stem cell factor (SCF). Using these cell lines, we observed that EpoR stimulation by Epo down-regulated expression of the SCF receptor Kit and induced expression of the Src kinase Lyn. Furthermore, enforced expression of Lyn in the cell lines increased cell proliferation in response to Epo, but reduced cell growth in response to SCF in accordance with Lyn ability to down-regulate Kit expression. Together, the data suggest that Epo-R/Lyn signaling pathway is essential for extinction of SCF signaling leading the proerythroblast to strict Epo dependency. These results highlight a new role for Lyn as an effector of EpoR in controlling Kit expression. They suggest that Lyn may play a central role in during erythroid differentiation at the switch between proliferation and maturation.
authors.affiliation: Inserm U830, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Kosmider
authors.forename: Dorothée
authors.initials: D
authors.lastname: Buet
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gallais
authors.forename: Nicole
authors.initials: N
authors.lastname: Denis
authors.forename: Françoise
authors.initials: F
authors.lastname: Moreau-Gachelin
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D004900:Erythroblasts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D004921:Erythropoietin / Q000494:pharmacology*; D007938:Leukemia / Q000201:enzymology*; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D017467:Receptors, Erythropoietin / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D016207:Cytokines; D004921:Erythropoietin; D050505:Mutant Proteins; D011518:Proto-Oncogene Proteins; D019009:Proto-Oncogene Proteins c-kit; D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D019061:src-Family Kinases; D000099232:Proto-Oncogene Protein Spi-1; C060902:lyn protein-tyrosine kinase