期刊
ONCOGENE
卷 26, 期 8, 页码 1188-1200出版社
SPRINGERNATURE
DOI: 10.1038/sj.onc.1209901
关键词
CML; eIF4F; mTOR; cap-dependent translation
资金
- NCI NIH HHS [R21 CA112936, R01 CA107041, 1R01 CA107041, R21 CA112936-01A1, 1R21 CA105514, R01 CA107041-01A1, R01 CA107041-02, R21 CA105514, 1R21 CA112936] Funding Source: Medline
- NIBIB NIH HHS [R01 EB004436] Funding Source: Medline
The oncogenic kinase Bcr-Abl is thought to cause chronic myelogenous leukemia (CML) by altering the transcription of specific genes with growth- and survival-promoting functions. Recently, Bcr-Abl has also been shown to activate an important regulator of protein synthesis, the mammalian target of rapamycin ( mTOR), which suggests that dysregulated translation may also contribute to CML pathogenesis. In this study, we found that both Bcr-Abl and the rapamycin-sensitive mTORC1 complex contribute to the phosphorylation ( inactivation) of 4E-BP1, an inhibitor of the eIF4E translation initiation factor. Experiments with rapamycin and the Bcr-Abl inhibitor, imatinib mesylate, in Bcr-Abl-expressing cell lines and primary CML cells indicated that Bcr-Abl and mTORC1 induced formation of the translation initiation complex, eIF4F. This was characterized by reduced 4E-BP1 binding and increased eIF4G binding to eIF4E, two events that lead to the assembly of eIF4F. One target transcript is cyclin D3, which is regulated in Bcr-Abl-expressing cells by both Bcr-Abl and mTORC1 in a translational manner. In addition, the combination of imatinib and rapamycin was found to act synergistically against committed CML progenitors from chronic and blast phase patients. These experiments establish a novel mechanism of action for Bcr-Abl, and they provide insights into the modes of action of imatinib mesylate and rapamycin in treatment of CML. They also suggest that aberrant cap-dependent mRNA translation may be a therapeutic target in BcrAbl-driven malignancies.
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