Abstract
The down-modulation of the β-catenin antagonist Chibby 1 (CBY1) associated with the BCR-ABL1 fusion gene of chronic myeloid leukemia (CML) contributes to the aberrant activation of β-catenin, particularly in leukemic stem cells (LSC) resistant to tyrosine kinase (TK) inhibitors. It is, at least partly, driven by transcriptional events and gene promoter hyper-methylation. Here we demonstrate that it also arises from reduced protein stability upon binding to 14-3-3σ adapter protein. CBY1/14-3-3σ interaction in BCR-ABL1+ cells is mediated by the fusion protein TK and AKT phosphorylation of CBY1 at critical serine 20, and encompasses the 14-3-3σ binding modes I and II involved in the binding with client proteins. Moreover, it is impaired by c-Jun N-terminal kinase (JNK) phosphorylation of 14-3-3σ at serine 186, which promotes dissociation of client proteins. The ubiquitin proteasome system UPS participates in reducing stability of CBY1 bound with 14-3-3σ through enhanced SUMOylation. Our results open new routes towards the research on molecular pathways promoting the proliferative advantage of leukemic hematopoiesis over the normal counterpart.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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14-3-3 Proteins / metabolism*
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Amino Acid Motifs
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Benzamides / pharmacology
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Biomarkers, Tumor / metabolism*
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Carrier Proteins / biosynthesis*
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Carrier Proteins / genetics
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Down-Regulation
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Exoribonucleases / metabolism*
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Fusion Proteins, bcr-abl / metabolism
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Gene Expression Regulation, Leukemic / genetics*
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Humans
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JNK Mitogen-Activated Protein Kinases / metabolism
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Nuclear Proteins / biosynthesis*
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Nuclear Proteins / genetics
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Oncogene Protein p65(gag-jun)
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Phosphorylation
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Proteasome Endopeptidase Complex / metabolism
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Protein Binding
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Protein Interaction Mapping
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Protein Processing, Post-Translational*
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Protein Stability
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Proto-Oncogene Proteins c-akt / metabolism
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Pyrazoles / pharmacology
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Subcellular Fractions / metabolism
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Sumoylation
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beta Catenin / antagonists & inhibitors
Substances
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14-3-3 Proteins
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BCR-ABL1 fusion protein, human
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BV02 compound
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Benzamides
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Biomarkers, Tumor
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CBY1 protein, human
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CTNNB1 protein, human
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Carrier Proteins
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Neoplasm Proteins
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Nuclear Proteins
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Oncogene Protein p65(gag-jun)
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Pyrazoles
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beta Catenin
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Fusion Proteins, bcr-abl
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AKT1 protein, human
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Proto-Oncogene Proteins c-akt
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JNK Mitogen-Activated Protein Kinases
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Exoribonucleases
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SFN protein, human
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Proteasome Endopeptidase Complex