RRC ID 43413
Author Yamane N, Takahashi K, Tanaka Y, Kato K, Takayama M, Ohyabu N, Shiota T, Takenaka H, Yoshida Y, Hara S, Murashi T, Nakamura E, Nishitani Y, Ishizaki J, Yamane S, Nagata K, Koizumi K, Yutsudo T, Suzuki R, Itoh T, Takemoto H.
Title Discovery of novel non-peptide thrombopoietin mimetic compounds that induce megakaryocytopoiesis.
Journal Biosci Rep
Abstract We have identified a series of novel non-peptide compounds that activate the thrombopoietin-dependent cell line Ba/F3-huMPL. The compounds stimulated proliferation of Ba/F3-huMPL in the absence of other growth factors, but did not promote proliferation of the thrombopoietin-independent parent cell line Ba/F3. The thrombopoietin-mimetic compounds elicited signal-transduction responses comparable with recombinant human thrombopoietin, such as tyrosine phosphorylation of the thrombopoietin receptor, JAK (Janus kinase) 2, Tyk2 (tyrosine kinase 2), STAT (signal transducer and activator of transcription) 3, STAT5, MAPKs (mitogen-activated protein kinases), PLCgamma (phospholipase Cgamma), Grb2 (growth-factor-receptor-bound protein 2), Shc (Src homology and collagen homology), Vav, Cbl and SHP-2 (Src homology 2 domain-containing protein tyrosine phosphatase 2) and increased the number of CD41(+) cells (megakaryocyte lineage) in cultures of human CD34(+) bone-marrow cells (haematopoietic stem cells). These findings suggest that this series of compounds are novel agonists of the human thrombopoietin receptor and are possible lead compounds for the generation of anti-thrombocytopaenia drugs.
Volume 28(5)
Pages 275-85
Published 2008-10-1
DOI 10.1042/BSR20080086
PII BSR20080086
PMID 18620546
MeSH Animals Biomimetic Materials / pharmacology* Bone Marrow Cells / cytology Bone Marrow Cells / metabolism* Cell Line GRB2 Adaptor Protein / biosynthesis Humans Mice Phospholipase C gamma / biosynthesis Protein Kinases / biosynthesis Protein Tyrosine Phosphatase, Non-Receptor Type 11 / biosynthesis Proto-Oncogene Proteins c-cbl / biosynthesis Proto-Oncogene Proteins c-vav / biosynthesis Receptors, Thrombopoietin / agonists* Receptors, Thrombopoietin / metabolism STAT3 Transcription Factor / biosynthesis STAT5 Transcription Factor / biosynthesis Shc Signaling Adaptor Proteins / biosynthesis Signal Transduction / drug effects* Thrombopoiesis / drug effects* Thrombopoietin / pharmacology*
IF 2.942
Times Cited 6
Human and Animal Cells Ba/F3(RCB0805)