title: Different roles of p38 MAPK and ERK in STI571-induced multi-lineage differentiation of K562 cells.
abstract: STI571 is a specific tyrosine kinase inhibitor of Abl kinase. It was previously reported that STI571 induced hemoglobin synthesis in the chronic myelogenous leukemia (CML) cell line K562. However, its mechanisms remain unknown. In this study, we demonstrated that STI571 induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and dephosphorylation of extracellular signal-regulated kinase (ERK) in K562 cells. In contrast, the phosphorylation of c-Jun N-terminal kinases (JNK) in K562 cells was not altered by STI571. We also found that STI571 induced all the myeloid (CD11b, CD13), megakaryocytic (CD41a, CD42), and erythroid (glycophorin-A) markers on K562 cells. A p38 MAPK-specific inhibitor, SB203580, inhibited the STI571-induced multi-lineage differentiation of K562 cells, indicating that p38 MAPK is crucial for this differentiation. In contrast, SB203580 did not overcome the inhibitory effect for proliferation of K562 cells, indicating that p38 MAPK activation by STI571 does not affect cell numbers. Among the hematopoietic transcription factors, the expression level of c-myb mRNA was clearly downregulated after incubation with STI571 in K562 cells. STI571-induced downregulation of c-myb mRNA was prevented by the pretreatment of K562 cells by SB203580. Our data provides insights into how p38 MAPK and ERK pathways are involved in STI571-induced differentiation of K562 cells.
authors.affiliation: Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Kanoko
authors.initials: K
authors.lastname: Kohmura
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Miyakawa
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kawai
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kizaki
mesh_terms: D001549:Benzamides; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006454:Hemoglobins / Q000096:biosynthesis / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D048031:JNK Mitogen-Activated Protein Kinases; D020014:K562 Cells; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D020598:Proto-Oncogene Proteins c-myb / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D001549:Benzamides; D015415:Biomarkers; D017931:DNA Primers; D004791:Enzyme Inhibitors; D006454:Hemoglobins; D010879:Piperazines; D020598:Proto-Oncogene Proteins c-myb; D011743:Pyrimidines; D014157:Transcription Factors; D000068877:Imatinib Mesylate; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases