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.

14-3-3 Binding and Sumoylation Concur to the Down-Modulation of β-catenin Antagonist chibby 1 in Chronic Myeloid Leukemia

MANCINI, MANUELA;LEO, ELISA;CAMPI, VIRGINIA;CASTAGNETTI, FAUSTO;SOVERINI, SIMONA;DE BENEDITTIS, CATERINA;ROSTI, GIANANTONIO;CAVO, MICHELE;SANTUCCI, MARIA ALESSANDRA;MARTINELLI, GIOVANNI
2015

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.
2015
Mancini, Manuela; Leo, Elisa; Takemaru, Ken-Ichi; Campi, Virginia; Castagnetti, Fausto; Soverini, Simona; De Benedittis, Caterina; Rosti, Gianantonio; Cavo, Michele; Santucci, Maria Alessandra; Martinelli, Giovanni
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Descrizione: S1 Fig: 14-3-3σ expression in our experimental model: 14-3-3σ expression exhibits slight differences in in the cytoplasmic and nuclear compartments of C22orf2 K562 cell line in response to drugs used to investigate differences in CBY1 expression relative to its interaction with 14-3-3σ
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Descrizione: S2 Fig: CBY1 transcriptional regulation after IM treatment: CBY1 increment in response to IM is driven by transcriptional mechanisms and conditional upon de-methylation of the C22orf2 promoter. A-Both CBY1 transcript isoforms (340 bp and 200 bp) were raised since 1st up to 5th h of IM treatment. B-5mC and DNMT1 recruitment at C22orf2 promoter were concurrently reduced in response to IM.
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Descrizione: S3 Fig: Drugs used to investigate CBY1 expression relative to its interaction with 14-3-3σ do not exhibit off target effec
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Descrizione: S4 Fig: CBY1 expression in the cytoplasmic and nuclear compartments of parental K562 cell line confirmed the results obtained in C22orf2 K562 cell line
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/528866
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