title: Small GTPase RAB45-mediated p38 activation in apoptosis of chronic myeloid leukemia progenitor cells.
abstract: Chronic myelogenous leukemia (CML) is characterized by a reciprocal chromosomal translocation (9;22) that generates the Bcr-Abl fusion gene. BCR-ABL transforming activity is mediated by critical downstream signaling pathways that are aberrantly activated by tyrosine kinases. However, the mechanisms of BCR-ABL anti-apoptotic effects and the signaling pathways by which BCR-ABL influences apoptosis in BCR-ABL-expressing cells are poorly defined. In this study, we found that treatment with ABL kinase inhibitors or depletion of BCR-ABL induced the expression of RAB45 messenger RNA and protein and induced apoptosis via reduction of mitochondrial membrane potential and p38 activation in CML cell lines and BCR-ABL(+) progenitor cells from CML patients. Overexpressed RAB45 induced the activation of caspases-3 and -9 and reduced the expression of Survivin, XIAP, c-IAP1 and c-IAP2 in CML cells. Moreover, in colony-forming cells derived from CML-aldehyde dehydrogenase(hi)/CD34(+) cells, treatment with ABL kinase inhibitors induced RAB45 expression and reduced mitochondrial membrane potential, resulting in inhibited colony formation of Bcr-Abl(+) progenitor cells. The overexpression of RAB45 significantly decreased colony numbers and induced apoptosis through the activation of caspases-3 and -9. Furthermore, the overexpression of RAB45 increased the phosphorylation levels of p38, resulting in the induction of apoptosis and inhibition of proliferation of CML progenitor cells. Our results identify a new signaling molecule involved in BCR-ABL modulation of apoptosis and suggest that RAB45 induction strategies may have therapeutic utility in patients with CML.
authors: Department of Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan. satonaka@hama-med.ac.jp
authors: Satoki
authors: S
authors: Nakamura
authors: Tomonari
authors: T
authors: Takemura
authors: Lin
authors: L
authors: Tan
authors: Yasuyuki
authors: Y
authors: Nagata
authors: Daisuke
authors: D
authors: Yokota
authors: Isao
authors: I
authors: Hirano
authors: Kazuyuki
authors: K
authors: Shigeno
authors: Kiyoshi
authors: K
authors: Shibata
authors: Michio
authors: M
authors: Fujie
authors: Shinya
authors: S
authors: Fujisawa
authors: Kazunori
authors: K
authors: Ohnishi
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017931:DNA Primers; D004789:Enzyme Activation; D016313:Genes, abl; D006801:Humans; D047468:Immunoprecipitation; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D008564:Membrane Potentials; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010766:Phosphorylation; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020663:ras Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D017931:DNA Primers; C529641:RASEF protein, human; D012333:RNA, Messenger; D020663:ras Guanine Nucleotide Exchange Factors; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3