title: Mechanisms for the proliferation of eosinophilic leukemia cells by FIP1L1-PDGFRalpha.
abstract: The constitutively activated tyrosine kinase Fip1-like 1 (FIP1L1)-platelet-derived growth factor receptor alpha (PDGFRalpha) causes eosinophilic leukemia EoL-1 cells to proliferate. Recently, we demonstrated that histone deacetylase inhibitors suppressed this proliferation and induced the differentiation of EoL-1 cells into eosinophils in parallel with a decrease in the level of FIP1L1-PDGFRalpha. In this study, we analyzed the mechanism by which FIP1L1-PDGFRalpha induces the proliferation and whether the suppression of cell proliferation triggers the differentiation into eosinophils. The FIP1L1-PDGFRalpha inhibitor imatinib inhibited the proliferation of EoL-1 cells and decreased the level of the oncoprotein c-Myc as well as the phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase (JNK). The proliferation of EoL-1 cells and expression of c-Myc were also inhibited by the MEK inhibitor U0126 and JNK inhibitor SP600125. The expression of the eosinophilic differentiation marker CCR3 was not induced by imatinib. These findings suggest that FIP1L1-PDGFRalpha induces the proliferation of EoL-1 cells through the induction of c-Myc expression via ERK and JNK signaling pathways, but is not involved in the inhibition of differentiation toward mature eosinophils.
authors: Laboratory of Pathophysiological Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
authors: Kenji
authors: K
authors: Ishihara
authors: Hajime
authors: H
authors: Kitamura
authors: Kenji
authors: K
authors: Hiraizumi
authors: Motoko
authors: M
authors: Kaneko
authors: Aki
authors: A
authors: Takahashi
authors: Okpyo
authors: O
authors: Zee
authors: Toshio
authors: T
authors: Seyama
authors: Jangja
authors: J
authors: Hong
authors: Kazuo
authors: K
authors: Ohuchi
authors: Noriyasu
authors: N
authors: Hirasawa
mesh_terms: D001549:Benzamides; D002070:Butadienes / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D017681:Hypereosinophilic Syndrome / Q000201:enzymology / Q000473:pathology*; D000068877:Imatinib Mesylate; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D054397:Receptors, CCR3 / Q000378:metabolism; D039221:mRNA Cleavage and Polyadenylation Factors / Q000378:metabolism*
chemical_list: D001549:Benzamides; D002070:Butadienes; D009570:Nitriles; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D016271:Proto-Oncogene Proteins c-myc; D011743:Pyrimidines; D054397:Receptors, CCR3; C113580:U 0126; D039221:mRNA Cleavage and Polyadenylation Factors; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020928:Mitogen-Activated Protein Kinases