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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.