title: 14-3-3 ligand prevents nuclear import of c-ABL protein in chronic myeloid leukemia.
abstract: Here we demonstrated that the 'loss of function' of not-rearranged c-ABL in chronic myeloid leukemia (CML) is promoted by its cytoplasmic compartmentalization bound to 14-3-3 sigma scaffolding protein. In particular, constitutive tyrosine kinase (TK) activity of p210 BCR-ABL blocks c-Jun N-terminal kinase (JNK) phosphorylation leading to 14-3-3 sigma phosphorylation at a critical residue (Ser(186)) for c-ABL binding in response to DNA damage. Moreover, it is associated with 14-3-3 sigma over-expression arising from epigenetic mechanisms (promoter hyper-acetylation). Accordingly, p210 BCR-ABL TK inhibition by the TK inhibitor Imatinib mesylate (IM) evokes multiple events, including JNK phosphorylation at Thr(183), p38 mitogen-activated protein kinase (MAPK) phosphorylation at Thr(180), c-ABL de-phosphorylation at Ser residues involved in 14-3-3 binding and reduction of 14-3-3 sigma expression, that let c-ABL release from 14-3-3 sigma and nuclear import, and address BCR-ABL-expressing cells towards apoptotic death. Informational spectrum method (ISM), a virtual spectroscopy method for analysis of protein interactions based on their structure, and mathematical filtering in cross spectrum (CS) analysis identified 14-3-3 sigma/c-ABL binding sites. Further investigation on CS profiles of c-ABL- and p210 BCR-ABL-containing complexes revealed the mechanism likely involved 14-3-3 precluded phosphorylation in CML cells.
authors.affiliation: Istituto di Ematologia e Oncologia Medica Lorenzo e Ariosto Serágnoli, University of Bologna-Medical School, Bologna, Italy. mancini_manu@yahoo.com
authors.forename: Manuela
authors.initials: M
authors.lastname: Mancini
authors.forename: Nevena
authors.initials: N
authors.lastname: Veljkovic
authors.forename: Valentina
authors.initials: V
authors.lastname: Corradi
authors.forename: Elisa
authors.initials: E
authors.lastname: Zuffa
authors.forename: Patrizia
authors.initials: P
authors.lastname: Corrado
authors.forename: Eleonora
authors.initials: E
authors.lastname: Pagnotta
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.forename: Enza
authors.initials: E
authors.lastname: Barbieri
authors.forename: Maria Alessandra
authors.initials: MA
authors.lastname: Santucci
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism*; D008024:Ligands; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D008024:Ligands; D016315:Proto-Oncogene Proteins c-abl; D048670:MAP Kinase Kinase 4