title: Fbxw7α- and GSK3-mediated degradation of p100 is a pro-survival mechanism in multiple myeloma.
abstract: Fbxw7α is a member of the F-box family of proteins, which function as the substrate-targeting subunits of SCF (Skp1/Cul1/F-box protein) ubiquitin ligase complexes. Using differential purifications and mass spectrometry, we identified p100, an inhibitor of NF-κB signalling, as an interactor of Fbxw7α. p100 is constitutively targeted in the nucleus for proteasomal degradation by Fbxw7α, which recognizes a conserved motif phosphorylated by GSK3. Efficient activation of non-canonical NF-κB signalling is dependent on the elimination of nuclear p100 through either degradation by Fbxw7α or exclusion by a newly identified nuclear export signal in the carboxy terminus of p100. Expression of a stable p100 mutant, expression of a constitutively nuclear p100 mutant, Fbxw7α silencing or inhibition of GSK3 in multiple myeloma cells with constitutive non-canonical NF-κB activity results in apoptosis both in cell systems and xenotransplant models. Thus, in multiple myeloma, Fbxw7α and GSK3 function as pro-survival factors through the control of p100 degradation.
authors.affiliation: NYU Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Busino
authors.forename: Scott E
authors.initials: SE
authors.lastname: Millman
authors.forename: Luigi
authors.initials: L
authors.lastname: Scotto
authors.forename: Christos A
authors.initials: CA
authors.lastname: Kyratsous
authors.forename: Venkatesha
authors.initials: V
authors.lastname: Basrur
authors.forename: Owen
authors.initials: O
authors.lastname: O'Connor
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
authors.forename: Kojo S
authors.initials: KS
authors.lastname: Elenitoba-Johnson
authors.forename: Michele
authors.initials: M
authors.lastname: Pagano
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism*; D002470:Cell Survival; D044783:F-Box Proteins / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology*; D052003:NF-kappa B p52 Subunit / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D052003:NF-kappa B p52 Subunit; D044767:Ubiquitin-Protein Ligases; D038362:Glycogen Synthase Kinase 3