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Sci. Signal., 4 December 2012
Vol. 5, Issue 253, p. pt14
[DOI: 10.1126/scisignal.2003408]

PRESENTATIONS

SCF-Mediated Degradation of p100 (NF-{kappa}B2): Mechanisms and Relevance in Multiple Myeloma

Luca Busino1*, Scott E. Millman1*, and Michele Pagano1,2{dagger}

1 NYU Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA.
2 Howard Hughes Medical Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA.

* These authors equally contributed to this work.

{dagger} Presenter and corresponding author. E-mail: michele.pagano{at}nyumc.org

A Presentation from the Sixth International Conference on SUMO, Ubiquitin and UBL proteins: Implications for Human Diseases, MD Anderson Cancer Center, Houston, Texas, 8 to 11 February 2012.

Abstract: On the basis of differential analysis of affinity purifications by mass spectrometry, we identified the nuclear factor {kappa}B (NF-{kappa}B) protein p100 (NF-{kappa}B2) as an interactor of the F-box protein FBXW7α. The NF-{kappa}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-{kappa}B pathway by sequestering NF-{kappa}B heterodimers in the cytoplasm. In the absence of NF-{kappa}B 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-{kappa}B 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-{kappa}B pathway, p100 is stabilized and retained in the nucleus, contributing to the cessation of noncanonical NF-{kappa}B signaling. The molecular mechanism of p100 degradation has implications in multiple myeloma, a disease with constitutive activation of the noncanonical NF-{kappa}B 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-{kappa}B activity.

Citation: L. Busino, S. E. Millman, M. Pagano, SCF-Mediated Degradation of p100 (NF-{kappa}B2): Mechanisms and Relevance in Multiple Myeloma. Sci. Signal. 5, pt14 (2012).

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