RRC ID 39251
Author Okajima Y, Matsumura I, Nishiura T, Hashimoto K, Yoshida H, Ishikawa J, Wakao H, Yoshimura A, Kanakura Y, Tomiyama Y, Matsuzawa Y.
Title Insulin-like growth factor-I augments erythropoietin-induced proliferation through enhanced tyrosine phosphorylation of STAT5.
Journal J Biol Chem
Abstract Insulin-like growth factor (IGF-I) is known to synergistically stimulate the proliferation of hematopoietic cells in combination with other hematopoietic growth factors. However, the precise mechanism underlying the cooperative effects of IGF-I is unknown. In a human interleukin-3 or erythropoietin (EPO)-dependent cell line, F-36P, IGF-I alone failed to stimulate DNA synthesis but did augment the EPO-dependent DNA synthesis of F-36P cells. The treatment of F-36P cells with a combination of EPO and IGF-I (EPO/IGF-I) was found to enhance EPO-induced tyrosine phosphorylation of STAT5, whereas IGF-I alone did not. Furthermore, c-CIS mRNA expression, one of the target molecules of STAT5, was more effectively induced by EPO/IGF-I than by EPO alone. To examine the mechanisms of the EPO- and EPO/IGF-I-induced proliferation of F-36P cells, we expressed dominant negative (dn) mutants of STAT5 and Ras in an inducible system. The EPO-induced DNA synthesis and the cooperative effect of EPO/IGF-I were significantly inhibited by the inducible expression of dn-STAT5 or dn-Ras. In addition, the inducible expression of dn-Ras abolished the IGF-I-enhanced tyrosine phosphorylation of STAT5. These results suggest that IGF-I may augment EPO-induced proliferation by enhancing tyrosine phosphorylation of STAT5 and raise the possibility that Ras may be involved in the augmentation of STAT5 tyrosyl phosphorylation.
Volume 273(36)
Pages 22877-83
Published 1998-9-4
DOI 10.1074/jbc.273.36.22877
PMID 9722506
MeSH Cell Division / drug effects DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism* Dose-Response Relationship, Drug Drug Synergism Erythropoietin / pharmacology* Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology Humans Insulin-Like Growth Factor I / pharmacology* Interleukin-3 / pharmacology Janus Kinase 2 Leukemia, Erythroblastic, Acute Milk Proteins* Mutation Phosphorylation Protein-Tyrosine Kinases / metabolism Proto-Oncogene Proteins* Recombinant Proteins / metabolism STAT5 Transcription Factor Signal Transduction Stem Cell Factor / pharmacology Trans-Activators / genetics Trans-Activators / metabolism* Transcriptional Activation Tumor Cells, Cultured Tyrosine / metabolism ras Proteins / metabolism
IF 4.106
Times Cited 27
Human and Animal Cells