Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin.
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.
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Division of Hematology/Oncology, Department of Medicine, College of Medicine, University of California, Irvine, California 92697, USA.
Arechiga
Adrian F
AF
Melo
Junia V
JV
Walsh
Craig M
CM
Ong
S Tiong
ST
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D004357:Drug Synergism; D039642:Eukaryotic Initiation Factors; D016044:Fusion Proteins, bcr-abl; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D038601:Ribosomal Protein S6 / Q000378:metabolism*; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D048868:Adaptor Proteins, Signal Transducing; D001549:Benzamides; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D039642:Eukaryotic Initiation Factors; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D011743:Pyrimidines; D038601:Ribosomal Protein S6; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C087000:EIF4EBP1 protein, human; C499527:Eif4ebp1 protein, mouse; C546842:MTOR protein, human; C546843:mTOR protein, mouse