Bcr-Abl ubiquitination and Usp9x inhibition block kinase signaling and promote CML cell apoptosis.

Although chronic myelogenous leukemia (CML) is effectively controlled by Bcr-Abl kinase inhibitors, resistance to inhibitors, progressive disease, and incomplete eradication of Bcr-Abl-expressing cells are concerns for the long-term control and suppression of this disease. We describe a novel approach to targeting key proteins in CML cells with a ubiquitin-cycle inhibitor, ...
WP1130. Bcr-Abl is rapidly modified with K63-linked ubiquitin polymers in WP1130-treated CML cells, resulting in its accumulation in aggresomes, where is it unable to conduct signal transduction. Induction of apoptosis because of aggresomal compartmentalization of Bcr-Abl was observed in both imatinib-sensitive and -resistant cells. WP1130, but not Bcr-Abl kinase inhibitors, directly inhibits Usp9x deubiquitinase activity, resulting in the down-regulation of the prosurvival protein Mcl-1 and facilitating apoptosis. These results demonstrate that ubiquitin-cycle inhibition represents a novel and effective approach to blocking Bcr-Abl kinase signaling and reducing Mcl-1 levels to engage CML cell apoptosis. This approach may be a therapeutic option for kinase inhibitor-resistant CML patients.
Mesh Terms:
Apoptosis, Cell Line, Tumor, Drug Resistance, Neoplasm, Endopeptidases, Fusion Proteins, bcr-abl, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Models, Biological, Nitriles, Phosphorylation, Piperazines, Protein Transport, Pyridines, Pyrimidines, Reactive Oxygen Species, Signal Transduction, Substrate Specificity, Ubiquitin Thiolesterase, Ubiquitination
Blood
Date: Mar. 17, 2011
Download Curated Data For This Publication
124961
Switch View:
  • Interactions 2
  • PTM Genes 1