title: Chibby drives β catenin cytoplasmic accumulation leading to activation of the unfolded protein response in BCR-ABL1+ cells.
abstract: Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by the constitutive tyrosine kinase (TK) activity of the BCR-ABL fusion protein. However, the phenotype of leukemic stem cells (LSC) is sustained by β catenin rather than by the BCR-ABL TK. β catenin activity in CML is contingent upon its stabilization proceeding from the BCR-ABL-induced phosphorylation at critical residues for interaction with the Adenomatous polyposis coli (APC)/Axin/glycogen synthase kinase 3 (GSK3) destruction complex or GSK3 inactivating mutations. Here we studied the impact of β catenin antagonist Chibby (CBY) on β catenin signaling in BCR-ABL1+ cells. CBY is a small conserved protein which interacts with β catenin and impairs β catenin-mediated transcriptional activation through two distinct molecular mechanisms: 1) competition with T cell factor (TCF) or lymphoid enhancer factor (LEF) for β catenin binding; and 2) nuclear export of β catenin via interaction with 14-3-3. We found that its enforced expression in K562 cell line promoted β catenin cytoplasmic translocation resulting in inhibition of target gene transcription. Moreover, cytoplasmic accumulation of β catenin activated the endoplasmic reticulum (ER) stress-associated pathway known as unfolded protein response (UPR). CBY-driven cytoplasmic accumulation of β catenin is also a component of BCR-ABL1+ cell response to the TK inhibitor Imatinib (IM). It evoked the UPR activation leading to the induction of BCL2-interacting mediator of cell death (BIM) by UPR sensors. BIM, in turn, contributed to the execution phase of apoptosis in the activation of ER resident caspase 12 and mobilization of Ca(2+) stores.
authors.affiliation: Department of Experimental Diagnostic and Specialty Medicine - DIMES - Institute of Hematology L and A Seràgnoli, University of Bologna-Medical School, Italy. mancini_manu@yahoo.com
authors.forename: Manuela
authors.initials: M
authors.lastname: Mancini
authors.forename: Elisa
authors.initials: E
authors.lastname: Leo
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Takemaru
authors.forename: Virginia
authors.initials: V
authors.lastname: Campi
authors.forename: Enrica
authors.initials: E
authors.lastname: Borsi
authors.forename: Fausto
authors.initials: F
authors.lastname: Castagnetti
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gugliotta
authors.forename: Maria Alessandra
authors.initials: MA
authors.lastname: Santucci
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D021381:Protein Transport; D056811:Unfolded Protein Response; D051176:beta Catenin / Q000032:analysis / Q000378:metabolism*
chemical_list: C473750:CBY1 protein, human; D002352:Carrier Proteins; D009687:Nuclear Proteins; D051176:beta Catenin