title: BCR-ABL suppresses autophagy through ATF5-mediated regulation of mTOR transcription.
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.
authors.affiliation: Howard Hughes Medical Institute, Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Sheng
authors.forename: Leyuan
authors.initials: L
authors.lastname: Ma
authors.forename: Jiaoyuan E
authors.initials: JE
authors.lastname: Sun
authors.forename: Lihua J
authors.initials: LJ
authors.lastname: Zhu
authors.forename: Michael R
authors.initials: MR
authors.lastname: Green
mesh_terms: D051696:Activating Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy; D001549:Benzamides; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D051696:Activating Transcription Factors; D000970:Antineoplastic Agents; D001549:Benzamides; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D007166:Immunosuppressive Agents; D008156:Luciferases; D019869:Phosphatidylinositol 3-Kinases; D010879:Piperazines; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D012333:RNA, Messenger; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C507532:ATF5 protein, human; C471855:Atf5 protein, mouse