Abstract
The oncoprotein BCR-ABL transforms myeloid progenitor cells and is responsible for the development of chronic myeloid leukemia (CML). In transformed cells, BCR-ABL suppresses apoptosis as well as autophagy, a catabolic process in which cellular components are degraded by the lysosomal machinery. The mechanism by which BCR-ABL suppresses autophagy is not known. Here we report that in both mouse and human BCR-ABL-transformed cells, activating transcription factor 5 (ATF5), a prosurvival factor, suppresses autophagy but does not affect apoptosis. We find that BCR-ABL, through PI3K/AKT/FOXO4 signaling, transcriptionally up-regulates ATF5 expression and that ATF5, in turn, stimulates transcription of mammalian target of rapamycin (mTOR; also called mechanistic target of rapamycin), a well-established master negative-regulator of autophagy. Previous studies have shown that the BCR-ABL inhibitor imatinib mesylate induces both apoptosis and autophagy, and that the resultant autophagy modulates the efficiency by which imatinib kills BCR-ABL-transformed cells. We demonstrate that imatinib-induced autophagy is because of inhibition of the BCR-ABL/PI3K/AKT/FOXO4/ATF5/mTOR pathway that we have identified in this study.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Activating Transcription Factors / antagonists & inhibitors
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Activating Transcription Factors / genetics
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Activating Transcription Factors / metabolism*
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Animals
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Antineoplastic Agents / pharmacology
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Autophagy*
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Benzamides
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Blotting, Western
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Cell Transformation, Neoplastic / metabolism
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Cell Transformation, Neoplastic / pathology
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Chromatin Immunoprecipitation
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Fusion Proteins, bcr-abl / metabolism*
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Gene Expression Regulation, Neoplastic*
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Humans
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Imatinib Mesylate
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Immunosuppressive Agents / pharmacology
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
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Luciferases / metabolism
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Mice
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / drug effects
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Piperazines / pharmacology
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Promoter Regions, Genetic / genetics
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Pyrimidines / pharmacology
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RNA, Messenger / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases / genetics*
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TOR Serine-Threonine Kinases / metabolism
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Transcription, Genetic
Substances
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ATF5 protein, human
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Activating Transcription Factors
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Antineoplastic Agents
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Atf5 protein, mouse
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Benzamides
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Immunosuppressive Agents
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Piperazines
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Pyrimidines
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RNA, Messenger
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Imatinib Mesylate
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Luciferases
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Fusion Proteins, bcr-abl
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Sirolimus