Small GTPase RAB45-mediated p38 activation in apoptosis of chronic myeloid leukemia progenitor cells
| Autor: | Isao Hirano, Tomonari Takemura, Kazunori Ohnishi, Satoki Nakamura, Kazuyuki Shigeno, Michio Fujie, Shinya Fujisawa, Daisuke Yokota, Kiyoshi Shibata, Yasuyuki Nagata, Lin Tan |
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| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Programmed cell death Blotting Western Apoptosis Genes abl Biology p38 Mitogen-Activated Protein Kinases Membrane Potentials Cell Line Tumor Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases Survivin medicine Humans Immunoprecipitation RNA Messenger Phosphorylation Progenitor cell neoplasms Cell Proliferation DNA Primers ABL Base Sequence Caspase 3 Reverse Transcriptase Polymerase Chain Reaction Cell Cycle General Medicine medicine.disease XIAP Enzyme Activation Neoplastic Stem Cells Cancer research RNA Interference ras Guanine Nucleotide Exchange Factors Signal transduction Stem cell Chronic myelogenous leukemia |
| Zdroj: | Carcinogenesis. 32:1758-1772 |
| ISSN: | 1460-2180 0143-3334 |
| DOI: | 10.1093/carcin/bgr205 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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