Fbxw7?- and GSK3-mediated degradation of p100 is a pro-survival mechanism in multiple myeloma.

ABSTRACT: Fbxw7? 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-?B signalling, as an interactor of Fbxw7?. p100 is constitutively targeted in the nucleus for proteasomal degradation by Fbxw7?, which recognizes a conserved motif phosphorylated by GSK3. Efficient activation of non-canonical NF-?B signalling is dependent on the elimination of nuclear p100 through either degradation by Fbxw7? 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, Fbxw7? silencing or inhibition of GSK3 in multiple myeloma cells with constitutive non-canonical NF-?B activity results in apoptosis both in cell systems and xenotransplant models. Thus, in multiple myeloma, Fbxw7? and GSK3 function as pro-survival factors through the control of p100 degradation.

SUBMITTER: Busino L 

PROVIDER: S-EPMC3339029 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature