Induction of autophagy by Imatinib sequesters Bcr-Abl in autophagosomes and down-regulates Bcr-Abl protein.
Authors
Elzinga, Baukje MNyhan, Michelle J
Crowley, Lisa C
O'Donovan, Tracey R
Cahill, Mary R
McKenna, Sharon L
Affiliation
Leslie C. Quick Laboratory, Cork Cancer Research Centre, BioSciences Institute, University College Cork, Cork, Ireland.Issue Date
2013-06MeSH
AdenineAnimals
Apoptosis Regulatory Proteins
Autophagy
Benzamides
Cell Line, Tumor
Down-Regulation
Fusion Proteins, bcr-abl
Gene Knockdown Techniques
Humans
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Membrane Proteins
Mice
Phagosomes
Piperazines
Proteasome Endopeptidase Complex
Protein Kinase Inhibitors
Pyrimidines
RNA, Small Interfering
Signal Transduction
Transfection
Metadata
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Induction of autophagy by Imatinib sequesters Bcr-Abl in autophagosomes and down-regulates Bcr-Abl protein. 2013, 88 (6):455-62 Am. J. Hematol.Journal
American journal of hematologyDOI
10.1002/ajh.23428PubMed ID
23440701Additional Links
http://onlinelibrary.wiley.com/doi/10.1002/ajh.23428/abstractAbstract
Chronic Myeloid Leukemia (CML) is a disease of hematopoietic stem cells which harbor the chimeric gene Bcr-Abl. Expression levels of this constitutively active tyrosine kinase are critical for response to tyrosine kinase inhibitor treatment and also disease progression, yet the regulation of protein stability is poorly understood. We have previously demonstrated that imatinib can induce autophagy in Bcr-Abl expressing cells. Autophagy has been associated with the clearance of large macromolecular signaling complexes and abnormal proteins, however, the contribution of autophagy to the turnover of Bcr-Abl protein in imatinib treated cells is unknown. In this study, we show that following imatinib treatment, Bcr-Abl is sequestered into vesicular structures that co-localize with the autophagy marker LC3 or GABARAP. This association is inhibited by siRNA mediated knockdown of autophagy regulators (Beclin 1/ATG7). Pharmacological inhibition of autophagy also reduced Bcr-Abl/LC3 co-localization in both K562 and CML patient cells. Bcr-Abl protein expression was reduced with imatinib treatment. Inhibition of both autophagy and proteasome activity in imatinib treated cells was required to restore Bcr-Abl protein levels to those of untreated cells. This ability to down-regulate Bcr-Abl protein levels through the induction of autophagy may be an additional and important feature of the activity of imatinib.Item Type
ArticleLanguage
enISSN
1096-8652ae974a485f413a2113503eed53cd6c53
10.1002/ajh.23428
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