title: Inactivation of ERK accelerates erythroid differentiation of K562 cells induced by herbimycin A and STI571 while activation of MEK1 interferes with it.
abstract: K562 cells contain a Bcr-Abl chimeric gene and differentiate into various lineages in response to different inducers. We studied the role of the mitogen-activated protein kinase (MAPK) kinase 1 (MEK1)/extracellular signal-regulated kinase (ERK) pathway during the erythroid differentiation of K562 cells induced by tyrosine kinase inhibitors (herbimycin A or STI571), using genetically modified cells (constitutively MEK1-activated K562: K562/MEK1, and inducible ERK-inactivated K562: K562/CL100). Basal expression of glycophorin A was markedly reduced in K562/MEK1 cells compared with that in parental cells, while it was augmented in K562/CL100 cells. Herbimycin A and STI571 differentiated K562 cells accompanying with the transient down-regulated ERK. Moreover, the erythroid differentiation was markedly suppressed in K562/MEK1 cells, and early down-regulation of ERK activity was not observed in these cells. In contrast, the induction of ERK-specific phosphatase in K562/CL100 cells potentiated erythroid differentiation. Once the phosphatase was induced, the initial ERK activity became repressed and its early down-regulation by the inhibition of Bcr-Abl was marked and prolonged. These results demonstrate that the erythroid differentiation of K562 cells induced by herbimycin A or STI571 requires the down-regulation of MEK1/ ERK pathway.
authors.affiliation: Department of Molecular Genetics, Institute of DNA Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kawano
authors.forename: Junko
authors.initials: J
authors.lastname: Horiguchi-Yamada
authors.forename: Satsuki
authors.initials: S
authors.lastname: Iwase
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Furukawa
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kano
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yamada
mesh_terms: D001549:Benzamides; D016227:Benzoquinones; D002454:Cell Differentiation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004900:Erythroblasts / Q000166:cytology / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006021:Glycophorins / Q000096:biosynthesis; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D047029:Lactams, Macrocyclic; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011809:Quinones / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
chemical_list: D001549:Benzamides; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D006021:Glycophorins; D047029:Lactams, Macrocyclic; D010879:Piperazines; D011743:Pyrimidines; D011809:Quinones; D011994:Recombinant Proteins; D017828:Rifabutin; C020754:herbimycin; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C096335:B59 protein, human; D017027:Protein Tyrosine Phosphatases