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Fbxw7α- and GSK3-mediated degradation of p100 is a pro-survival mechanism in multiple myeloma.

Nature cell biology | Apr 3, 2012

http://www.ncbi.nlm.nih.gov/pubmed/22388891

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.

Pubmed ID: 22388891 RIS Download

Mesh terms: Cell Cycle Proteins | Cell Survival | F-Box Proteins | Glycogen Synthase Kinase 3 | HEK293 Cells | HeLa Cells | Humans | Multiple Myeloma | NF-kappa B p52 Subunit | Tumor Cells, Cultured | Ubiquitin-Protein Ligases

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Associated grants

  • Agency: NHLBI NIH HHS, Id: 5T32HL007151-33
  • Agency: NIGMS NIH HHS, Id: R01 GM057587
  • Agency: NIGMS NIH HHS, Id: R01 GM057587-13
  • Agency: NIGMS NIH HHS, Id: R01 GM057587-14
  • Agency: NIGMS NIH HHS, Id: R01-GM057587
  • Agency: NCI NIH HHS, Id: R21 CA161108
  • Agency: NCI NIH HHS, Id: R21 CA161108-01
  • Agency: NCI NIH HHS, Id: R21-CA161108
  • Agency: NCI NIH HHS, Id: R37 CA076584
  • Agency: NCI NIH HHS, Id: R37 CA076584-13
  • Agency: NCI NIH HHS, Id: R37 CA076584-14
  • Agency: NCI NIH HHS, Id: R37-CA076584
  • Agency: NCI NIH HHS, Id: T32 CA009161
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

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