SEL-10 Is an Inhibitor of Notch Signaling That Targets Notch for Ubiquitin-Mediated Protein Degradation

Abstract

Notch receptors and their ligands play important roles in both normal animal development and pathogenesis. We show here that the F-box/WD40 repeat protein SEL-10 negatively regulates Notch receptor activity by targeting the intracellular domain of Notch receptors for ubiquitin-mediated protein degradation. Blocking of endogenous SEL-10 activity was done by expression of a dominant-negative form containing only the WD40

Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy

“…This finding explains the frequently elevated expression of cyclin E in breast tumors lacking active Fbw7 (Ekholm-Reed et al, 2004). Other substrates include the oncoproteins c-Myc (Moberg et al, 2004;Welcker et al, 2004;Yada et al, 2004), c-Jun (Nateri et al, 2004;Wei et al, 2005) and Notch (Gupta-Rossi et al, 2001;Oberg et al, 2001;Wu et al, 2001), all of which act to increase cell volume, proliferation and de-differentiation. In addition, Aurora A kinase, an important regulator of mitosis that is frequently overexpressed in human cancer tissues, also serves as a substrate of Fbw7 (Mao et al, 2004;Fujii et al, 2006).…”

Induction of apoptosis by proteasome inhibitors in B-CLL cells is associated with downregulation of CD23 and inactivation of Notch2

“…[21][22][23][24] The ubiquitin-proteasome pathway is the major extra-lysosomal machinery for protein degradation and is involved in the regulation of cell growth, apoptosis, and gene expression. 25,26 Proteins are specifically targeted for destruction by the 26S proteasome through the addition of polyubiquitin chains consisting of at least four ubiquitin polypeptides.…”

Notch4 intracellular domain binding to Smad3 and inhibition of the TGF-β signaling

“…The MH2 domain regulates Smad oligomerization, recognizes Type I receptors and interacts with cytoplasmic adaptors and several transcriptional factors such as p300 (Moustakas et al, 2001). To ascertain which domain of Smad3 binds to ICD4, we cotransfected a HaHis-tagged ICD4 expression vector (Wu et al, 2001) with a Flag-tagged MH1 Smad3 or a Flag-tagged MH2 Smad3 expression construct into Bosc 23 cells. The extracts were immunoprecipitated with an anti-Flag antibody to pull down the Smad3 proteins and immunobloted with anti-ICD4 antibody.…”

“…ICD4 and dRAM-ICD4 protein expression was induced for 16 h with 10 nM mifepristone in NIH3T3 cells. The HAHis-tagged mouse ICD4 was kindly provided by Jan Kitajewski, Columbia University (Wu et al, 2001). Human Notch1ICD was kindly provided by Anthony J Capobianco, University of Pennsylvania (Capobianco et al, 1997).…”