| Literature DB >> 21725355 |
I Hayashi1, S Takatori1, Y Urano2, Y Miyake3, J Takagi4, M Sakata-Yanagimoto3, H Iwanari2,5, S Osawa1, Y Morohashi1, T Li6, P C Wong6, S Chiba3, T Kodama2, T Hamakubo2, T Tomita1,7, T Iwatsubo1,7,8.
Abstract
Several lines of evidence suggest that aberrant Notch signaling contributes to the development of several types of cancer. Activation of Notch receptor is executed through intramembrane proteolysis by γ-secretase, which is a multimeric membrane-embedded protease comprised of presenilin, nicastrin (NCT), anterior pharynx defective 1 and PEN-2. In this study, we report the neutralization of the γ-secretase activity by a novel monoclonal antibody A5226A against the extracellular domain of NCT, generated by using a recombinant budded baculovirus as an immunogen. This antibody recognized fully glycosylated mature NCT in the active γ-secretase complex on the cell surface, and inhibited the γ-secretase activity by competing with the substrate binding in vitro. Moreover, A5226A abolished the γ-secretase activity-dependent growth of cancer cells in a xenograft model. Our data provide compelling evidence that NCT is a molecular target for the mechanism-based inhibition of γ-secretase, and that targeting NCT might be a novel therapeutic strategy against cancer caused by aberrant γ-secretase activity and Notch signaling.Entities:
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Year: 2011 PMID： 21725355 PMCID： PMC4058788 DOI： 10.1038/onc.2011.265
Source DB: PubMed Journal: Oncogene ISSN： 0950-9232 Impact factor: 9.867