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dc.contributor.authorElzinga, Baukje M
dc.contributor.authorNyhan, Michelle J
dc.contributor.authorCrowley, Lisa C
dc.contributor.authorO'Donovan, Tracey R
dc.contributor.authorCahill, Mary R
dc.contributor.authorMcKenna, Sharon L
dc.date.accessioned2014-07-03T14:10:07Z
dc.date.available2014-07-03T14:10:07Z
dc.date.issued2013-06
dc.identifier.citationInduction of autophagy by Imatinib sequesters Bcr-Abl in autophagosomes and down-regulates Bcr-Abl protein. 2013, 88 (6):455-62 Am. J. Hematol.en_GB
dc.identifier.issn1096-8652
dc.identifier.pmid23440701
dc.identifier.doi10.1002/ajh.23428
dc.identifier.urihttp://hdl.handle.net/10147/322353
dc.description.abstractChronic 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.
dc.language.isoenen
dc.relation.urlhttp://onlinelibrary.wiley.com/doi/10.1002/ajh.23428/abstracten_GB
dc.rightsArchived with thanks to American journal of hematologyen_GB
dc.subject.meshAdenine
dc.subject.meshAnimals
dc.subject.meshApoptosis Regulatory Proteins
dc.subject.meshAutophagy
dc.subject.meshBenzamides
dc.subject.meshCell Line, Tumor
dc.subject.meshDown-Regulation
dc.subject.meshFusion Proteins, bcr-abl
dc.subject.meshGene Knockdown Techniques
dc.subject.meshHumans
dc.subject.meshK562 Cells
dc.subject.meshLeukemia, Myelogenous, Chronic, BCR-ABL Positive
dc.subject.meshMembrane Proteins
dc.subject.meshMice
dc.subject.meshPhagosomes
dc.subject.meshPiperazines
dc.subject.meshProteasome Endopeptidase Complex
dc.subject.meshProtein Kinase Inhibitors
dc.subject.meshPyrimidines
dc.subject.meshRNA, Small Interfering
dc.subject.meshSignal Transduction
dc.subject.meshTransfection
dc.titleInduction of autophagy by Imatinib sequesters Bcr-Abl in autophagosomes and down-regulates Bcr-Abl protein.en_GB
dc.typeArticleen
dc.contributor.departmentLeslie C. Quick Laboratory, Cork Cancer Research Centre, BioSciences Institute, University College Cork, Cork, Ireland.en_GB
dc.identifier.journalAmerican journal of hematologyen_GB
dc.description.fundingHEA Higher Education Authorityen
dc.description.provinceMunsteren
dc.description.peer-reviewpeer-reviewen
html.description.abstractChronic 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.


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