BCR-ABL suppresses autophagy through ATF5-mediated regulation of mTOR transcription
Program in Gene Function and Expression; Program in Molecular Medicine
Fusion Proteins, bcr-abl; Activating Transcription Factors; TOR Serine-Threonine Kinases; Autophagy
Genetics and Genomics
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.
DOI of Published Version
Blood. 2011 Jun 29. Link to article on publisher's site
Sheng Z, Ma L, Sun J, Zhu LJ, Green MR. (2011). BCR-ABL suppresses autophagy through ATF5-mediated regulation of mTOR transcription. Program in Gene Function and Expression Publications. https://doi.org/10.1182/blood-2010-12-322537. Retrieved from https://escholarship.umassmed.edu/pgfe_pp/168