title: 14-3-3 Binding and Sumoylation Concur to the Down-Modulation of β-catenin Antagonist chibby 1 in Chronic Myeloid Leukemia.
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.
authors.affiliation: Department of Experimental Diagnostic and Specialty Medicine-DIMES-Institute of Hematology "L. and A. Seràgnoli". University of Bologna-Medical School, Bologna, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Mancini
authors.affiliation: Department of Experimental Diagnostic and Specialty Medicine-DIMES-Institute of Hematology "L. and A. Seràgnoli". University of Bologna-Medical School, Bologna, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Leo
authors.affiliation: Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York, United States of America.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Takemaru
authors.affiliation: Department of Experimental Diagnostic and Specialty Medicine-DIMES-Institute of Hematology "L. and A. Seràgnoli". University of Bologna-Medical School, Bologna, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: Campi
authors.affiliation: Department of Experimental Diagnostic and Specialty Medicine-DIMES-Institute of Hematology "L. and A. Seràgnoli". University of Bologna-Medical School, Bologna, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Castagnetti
authors.affiliation: Department of Experimental Diagnostic and Specialty Medicine-DIMES-Institute of Hematology "L. and A. Seràgnoli". University of Bologna-Medical School, Bologna, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Soverini
authors.affiliation: Department of Experimental Diagnostic and Specialty Medicine-DIMES-Institute of Hematology "L. and A. Seràgnoli". University of Bologna-Medical School, Bologna, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: De Benedittis
authors.affiliation: Department of Experimental Diagnostic and Specialty Medicine-DIMES-Institute of Hematology "L. and A. Seràgnoli". University of Bologna-Medical School, Bologna, Italy.
authors.forename: Gianantonio
authors.initials: G
authors.lastname: Rosti
authors.affiliation: Department of Experimental Diagnostic and Specialty Medicine-DIMES-Institute of Hematology "L. and A. Seràgnoli". University of Bologna-Medical School, Bologna, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Cavo
authors.affiliation: Department of Experimental Diagnostic and Specialty Medicine-DIMES-Institute of Hematology "L. and A. Seràgnoli". University of Bologna-Medical School, Bologna, Italy.
authors.forename: Maria Alessandra
authors.initials: MA
authors.lastname: Santucci
authors.affiliation: Department of Experimental Diagnostic and Specialty Medicine-DIMES-Institute of Hematology "L. and A. Seràgnoli". University of Bologna-Medical School, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D020816:Amino Acid Motifs; D001549:Benzamides / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation; D005095:Exoribonucleases / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D016759:Oncogene Protein p65(gag-jun); D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D013347:Subcellular Fractions / Q000378:metabolism; D058207:Sumoylation; D051176:beta Catenin / Q000037:antagonists & inhibitors
chemical_list: D048948:14-3-3 Proteins; C581634:BCR-ABL1 fusion protein, human; C557642:BV02 compound; D001549:Benzamides; D014408:Biomarkers, Tumor; C473750:CBY1 protein, human; C495270:CTNNB1 protein, human; D002352:Carrier Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D016759:Oncogene Protein p65(gag-jun); D011720:Pyrazoles; D051176:beta Catenin; D016044:Fusion Proteins, bcr-abl; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D005095:Exoribonucleases; C413442:SFN protein, human; D046988:Proteasome Endopeptidase Complex