Sci. Signal., 4 December 2012
SCF-Mediated Degradation of p100 (NF-B2): Mechanisms and Relevance in Multiple Myeloma
1 NYU Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA.
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 B (NF-B) protein p100 (NF-B2) as an interactor of the F-box protein FBXW7α. 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 FBXW7α, 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 FBXW7α-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, 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-B activity.
Citation: L. Busino, S. E. Millman, M. Pagano, SCF-Mediated Degradation of p100 (NF-B2): Mechanisms and Relevance in Multiple Myeloma. Sci. Signal. 5, pt14 (2012).
The editors suggest the following Related Resources on Science sites:
In Science Signaling
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882