| http://purl.uniprot.org/citations/12388777 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/12388777 | http://www.w3.org/2000/01/rdf-schema#comment | "Presenilin 1 (PS1), presenilin 2, and nicastrin form high molecular weight complexes that are necessary for the endoproteolysis of several type 1 transmembrane proteins, including amyloid precursor protein (APP) and the Notch receptor, by apparently similar mechanisms. The cleavage of the Notch receptor at the "S3-site" releases a C-terminal cytoplasmic fragment (Notch intracellular domain) that acts as the intracellular transduction molecule for Notch activation. Missense mutations in the presenilins cause familial Alzheimer's disease by augmenting the "gamma-secretase" cleavage of APP and overproducing one of the proteolytic derivatives, the Abeta peptide. Null mutations in PS1 inhibit both gamma-secretase cleavage of APP and S3-site cleavage of the Notch receptor. Mice lacking PS1 function have defective Notch signaling and die perinatally with severe skeletal and brain deformities. We report here that a genetic modifier on mouse distal chromosome 1, coinciding with the locus containing Nicastrin, influences presenilin-mediated Notch S3-site cleavage and the resultant Notch phenotype without affecting presenilin-mediated APP gamma-site cleavage. Two missense substitutions of residues conserved among vertebrates have been identified in nicastrin. These results indicate that Notch S3-site cleavage and APP gamma-site cleavage are distinct presenilin-dependent processes and support a functional interaction between nicastrin and presenilins in vertebrates. The dissociation of Notch S3-site and APP gamma-site cleavage activities will facilitate development of gamma-secretase inhibitors for treatment of Alzheimer's disease."xsd:string |
| http://purl.uniprot.org/citations/12388777 | http://purl.org/dc/terms/identifier | "doi:10.1073/pnas.222413999"xsd:string |
| http://purl.uniprot.org/citations/12388777 | http://purl.uniprot.org/core/author | "Chen F."xsd:string |
| http://purl.uniprot.org/citations/12388777 | http://purl.uniprot.org/core/author | "Gu Y."xsd:string |
| http://purl.uniprot.org/citations/12388777 | http://purl.uniprot.org/core/author | "Huang J."xsd:string |
| http://purl.uniprot.org/citations/12388777 | http://purl.uniprot.org/core/author | "Yu G."xsd:string |
| http://purl.uniprot.org/citations/12388777 | http://purl.uniprot.org/core/author | "Rozmahel R."xsd:string |
| http://purl.uniprot.org/citations/12388777 | http://purl.uniprot.org/core/author | "Nguyen V."xsd:string |
| http://purl.uniprot.org/citations/12388777 | http://purl.uniprot.org/core/author | "St George-Hyslop P."xsd:string |
| http://purl.uniprot.org/citations/12388777 | http://purl.uniprot.org/core/author | "Hasegawa H."xsd:string |
| http://purl.uniprot.org/citations/12388777 | http://purl.uniprot.org/core/author | "Nixon R.A."xsd:string |
| http://purl.uniprot.org/citations/12388777 | http://purl.uniprot.org/core/author | "Song Y.Q."xsd:string |
| http://purl.uniprot.org/citations/12388777 | http://purl.uniprot.org/core/author | "Mathews P.M."xsd:string |
| http://purl.uniprot.org/citations/12388777 | http://purl.uniprot.org/core/author | "Westaway D."xsd:string |
| http://purl.uniprot.org/citations/12388777 | http://purl.uniprot.org/core/author | "Bergeron C."xsd:string |
| http://purl.uniprot.org/citations/12388777 | http://purl.uniprot.org/core/author | "Fraser P."xsd:string |
| http://purl.uniprot.org/citations/12388777 | http://purl.uniprot.org/core/author | "Schmidt S.D."xsd:string |
| http://purl.uniprot.org/citations/12388777 | http://purl.uniprot.org/core/author | "Mount H.T."xsd:string |
| http://purl.uniprot.org/citations/12388777 | http://purl.uniprot.org/core/author | "Liauw J."xsd:string |
| http://purl.uniprot.org/citations/12388777 | http://purl.uniprot.org/core/author | "Erdebil S."xsd:string |
| http://purl.uniprot.org/citations/12388777 | http://purl.uniprot.org/core/date | "2002"xsd:gYear |
| http://purl.uniprot.org/citations/12388777 | http://purl.uniprot.org/core/name | "Proc Natl Acad Sci U S A"xsd:string |
| http://purl.uniprot.org/citations/12388777 | http://purl.uniprot.org/core/pages | "14452-14457"xsd:string |
| http://purl.uniprot.org/citations/12388777 | http://purl.uniprot.org/core/title | "Alleles at the Nicastrin locus modify presenilin 1- deficiency phenotype."xsd:string |