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    BCR-ABL suppresses autophagy through ATF5-mediated regulation of mTOR transcription

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    Authors
    Sheng, Zhi
    Ma, Leyuan
    Sun, Jiaoyuan
    Zhu, Lihua Julie
    Green, Michael R.
    UMass Chan Affiliations
    Program in Molecular Medicine
    Program in Gene Function and Expression
    Document Type
    Journal Article
    Publication Date
    2011-06-29
    Keywords
    Fusion Proteins, bcr-abl
    Activating Transcription Factors
    TOR Serine-Threonine Kinases
    Autophagy
    Genetics and Genomics
    
    Metadata
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    Link to Full Text
    http://dx.doi.org/10.1182/blood-2010-12-322537
    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 pro-survival factor, suppresses autophagy but does not affect apoptosis. We find that BCR-ABL, through phosphoinositide-3-kinase (PI3K)/AKT/FOXO4 signaling, transcriptionally upregulates 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 due to inhibition of the BCR-ABL/PI3K/AKT/FOXO4/ATF5/mTOR pathway that we have identified in this study.
    Source
    Blood. 2011 Jun 29. Link to article on publisher's site
    DOI
    10.1182/blood-2010-12-322537
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/43957
    PubMed ID
    21715304
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1182/blood-2010-12-322537
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