• Register
X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

X

Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.

No
Yes

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

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

Authors

  • Busino L
  • Millman SE
  • Scotto L
  • Kyratsous CA
  • Basrur V
  • O'Connor O
  • Hoffmann A
  • Elenitoba-Johnson KS
  • Pagano M

Journal

Nature cell biology

Publication Data

April 3, 2012

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: NIGMS NIH HHS, Id: T32 GM007308
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

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