Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin
| Autor: | Chi, Ly, Adrian F, Arechiga, Junia V, Melo, Craig M, Walsh, S Tiong, Ong |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Fusion Proteins
bcr-abl Apoptosis Cell Cycle Proteins Piperazines Mice Phosphatidylinositol 3-Kinases Leukemia Myelogenous Chronic BCR-ABL Positive Antineoplastic Combined Chemotherapy Protocols Animals Humans Eukaryotic Initiation Factors Phosphorylation Protein Kinase Inhibitors Adaptor Proteins Signal Transducing Sirolimus Ribosomal Protein S6 TOR Serine-Threonine Kinases Drug Synergism Protein-Tyrosine Kinases Hematopoietic Stem Cells Phosphoproteins Pyrimidines Benzamides Imatinib Mesylate Carrier Proteins K562 Cells Protein Kinases |
| Zdroj: | Cancer research. 63(18) |
| ISSN: | 0008-5472 |
| Popis: | Identification of signaling pathways downstream of Abl tyrosine kinase may increase our understanding of the pathogenesis of chronic myelogenous leukemia (CML) and suggest strategies to improve clinical treatment of the disease. By combining the use of a phosphospecific antibody recognizing a substrate motif of serine/threonine kinases with bioinformatics, we found that the translational regulators ribosomal protein S6 and 4E-BP1 are constitutively phosphorylated in CML cells. Experiments with specific inhibitors indicated the phosphorylation is downstream of Bcr-Abl kinase and the mammalian target of rapamycin (mTOR). These results suggest that Bcr-Abl may regulate translation of critical targets in CML cells via mTOR. They also provide a rationale for testing the combination of mTOR inhibitors with the Abl kinase inhibitor imatinib in patients with CML. The mTOR inhibitor rapamycin enhanced imatinib-mediated killing of CML cell lines in vitro, and it overcame imatinib resistance in cells with Bcr-Abl gene amplification. |
| Databáze: | OpenAIRE |
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