title: Reduction of Raf kinase inhibitor protein expression by Bcr-Abl contributes to chronic myelogenous leukemia proliferation.
abstract: Chronic myelogenous leukemia (CML) is characterized by a reciprocal chromosomal translocation (9;22) that generates the Bcr-Abl fusion gene. The Ras/Raf-1/MEK/ERK pathway is constitutively activated in Bcr-Abl-transformed cells, and Ras activity enhances the oncogenic ability of Bcr-Abl. However, the mechanism by which Bcr-Abl activates the Ras pathway is not completely understood. Raf kinase inhibitor protein (RKIP) inhibits activation of MEK by Raf-1 and its downstream signal transduction, resulting in blocking the MAP kinase pathway. In the present study, we found that RKIP was depleted in CML cells. We investigated the interaction between RKIP and Bcr-Abl in CML cell lines and Bcr-Abl(+) progenitor cells from CML patients. The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of RKIP and reduced the pERK1/2 status, resulting in inhibited proliferation of CML cells. Moreover, RKIP up-regulated cell cycle regulator FoxM1 expression, resulting in G(1) arrest via p27(Kip1) and p21(Cip1) accumulation. In colony-forming unit granulocyte, erythroid, macrophage, megakaryocyte, colony-forming unit-granulocyte macrophage, and burst-forming unit erythroid, treatment with the Abl kinase inhibitors and depletion of Bcr-Abl induced RKIP and reduced FoxM1 expressions, and inhibited colony formation of Bcr-Abl(+) progenitor cells, whereas depletion of RKIP weakened the inhibition of colony formation activity by the Abl kinase inhibitors in Bcr-Abl(+) progenitor cells. Thus, Bcr-Abl represses the expression of RKIP, continuously activates pERK1/2, and suppresses FoxM1 expression, resulting in proliferation of CML cells.
authors.affiliation: Department of Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan.
authors.forename: Tomonari
authors.initials: T
authors.lastname: Takemura
authors.forename: Satoki
authors.initials: S
authors.lastname: Nakamura
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yokota
authors.forename: Isao
authors.initials: I
authors.lastname: Hirano
authors.forename: Takaaki
authors.initials: T
authors.lastname: Ono
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Shigeno
authors.forename: Shinya
authors.initials: S
authors.lastname: Fujisawa
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ohnishi
mesh_terms: D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D049488:Phosphatidylethanolamine Binding Protein / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013234:Stem Cells / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D049488:Phosphatidylethanolamine Binding Protein; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl; D048052:Mitogen-Activated Protein Kinase 3