title: SCF-mediated degradation of p100 (NF-κB2): mechanisms and relevance in multiple myeloma.
abstract: On the basis of differential analysis of affinity purifications by mass spectrometry, we identified the nuclear factor κB (NF-κB) protein p100 (NF-κB2) as an interactor of the F-box protein FBXW7α. The NF-κB pathway is important for cell growth, differentiation, and survival. p100, which shuttles between the cytoplasm and nucleus, functions as the primary inhibitor of the noncanonical NF-κB pathway by sequestering NF-κB heterodimers in the cytoplasm. In the absence of NF-κB stimulation, the nuclear pool of p100 is constitutively targeted for degradation by FBXW7α, which recognizes a conserved motif that is phosphorylated by glycogen synthase kinase 3 (GSK3). Efficient activation of noncanonical NF-κB signaling depends on the clearance of nuclear p100, either through FBXW7α-mediated degradation or nuclear export mediated by a signal in the C terminus of p100. Upon prolonged stimulation of the NF-κB pathway, p100 is stabilized and retained in the nucleus, contributing to the cessation of noncanonical NF-κB signaling. The molecular mechanism of p100 degradation has implications in multiple myeloma, a disease with constitutive activation of the noncanonical NF-κB pathway. Accordingly, expression of a stable p100 mutant, FBXW7α depletion, or chemical inhibition of GSK3 in multiple myeloma cells results in cell death in vitro and in a xenotransplant model. Thus, the FBXW7α-dependent degradation of p100 functions as a prosurvival mechanism through control of NF-κB activity.
authors.affiliation: NYU Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Busino
authors.affiliation: NYU Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Millman
authors.affiliation: NYU Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA.|Howard Hughes Medical Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Pagano
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D059748:Proteolysis; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / 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; C498206:NFKB2 protein, human; D009363:Neoplasm Proteins; D044843:SKP Cullin F-Box Protein Ligases; D044767:Ubiquitin-Protein Ligases; D038362:Glycogen Synthase Kinase 3