SCF-mediated degradation of p100 (NF-?B2): mechanisms and relevance in multiple myeloma.

ABSTRACT: On the basis of differential analysis of affinity purifications by mass spectrometry, we identified the nuclear factor ?B (NF-?B) protein p100 (NF-?B2) as an interactor of the F-box protein FBXW7?. The NF-?B 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-?B pathway by sequestering NF-?B heterodimers in the cytoplasm. In the absence of NF-?B stimulation, the nuclear pool of p100 is constitutively targeted for degradation by FBXW7?, which recognizes a conserved motif that is phosphorylated by glycogen synthase kinase 3 (GSK3). Efficient activation of noncanonical NF-?B signaling depends on the clearance of nuclear p100, either through FBXW7?-mediated degradation or nuclear export mediated by a signal in the C terminus of p100. Upon prolonged stimulation of the NF-?B pathway, p100 is stabilized and retained in the nucleus, contributing to the cessation of noncanonical NF-?B signaling. The molecular mechanism of p100 degradation has implications in multiple myeloma, a disease with constitutive activation of the noncanonical NF-?B pathway. Accordingly, expression of a stable p100 mutant, FBXW7? depletion, or chemical inhibition of GSK3 in multiple myeloma cells results in cell death in vitro and in a xenotransplant model. Thus, the FBXW7?-dependent degradation of p100 functions as a prosurvival mechanism through control of NF-?B activity.

SUBMITTER: Busino L 

PROVIDER: S-EPMC3871187 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature