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Titolo:
Endoproteolysis of the ER stress transducer ATF6 in the presence of functionally inactive presenilins
Autore:
Steiner, H; Winkler, E; Shearman, MS; Prywes, R; Haass, C;
Indirizzi:
Univ Munich, Adolf Butenandt Inst, Dept Biochem, Lab Alzheimers & Parkinsons Dis Res, D-80336 Munich, Germany Univ Munich Munich Germany D-80336 sons Dis Res, D-80336 Munich, Germany Merck Sharp & Dohme Res Labs, Dept Biol Mol, Ctr Res Neurosci, Harlow CM202QR, Essex, England Merck Sharp & Dohme Res Labs Harlow Essex England CM202QR Essex, England Columbia Univ, Dept Biol Sci, New York, NY 10027 USA Columbia Univ New York NY USA 10027 Dept Biol Sci, New York, NY 10027 USA
Titolo Testata:
NEUROBIOLOGY OF DISEASE
fascicolo: 4, volume: 8, anno: 2001,
pagine: 717 - 722
SICI:
0969-9961(200108)8:4<717:EOTEST>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
UNFOLDED-PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM STRESS; GAMMA-SECRETASE INHIBITORS; AMYLOID PRECURSOR PROTEIN; INTRAMEMBRANE PROTEOLYSIS; NOTCH; ACCUMULATION; DEFICIENCY; CLEAVAGE; MUTATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
26
Recensione:
Indirizzi per estratti:
Indirizzo: Steiner, H Univ Munich, Adolf Butenandt Inst, Dept Biochem, Lab Alzheimers& Parkinsons Dis Res, D-80336 Munich, Germany Univ Munich Munich GermanyD-80336 s, D-80336 Munich, Germany
Citazione:
H. Steiner et al., "Endoproteolysis of the ER stress transducer ATF6 in the presence of functionally inactive presenilins", NEUROBIOL D, 8(4), 2001, pp. 717-722

Abstract

Presenilin (PS) proteins facilitate endoproteolysis of selected type I transmembrane proteins such as the Alzheimer's disease (AD) associated beta -Amyloid precursor protein (beta APP) and Notch. beta APP is cleaved within its transmembrane domain by an aspartyl protease activity termed gamma -secretase, which may be identical with PS1 and PS2. Notch also undergoes a PS-dependent intramembraneous proteolysis. A similar gamma -secretase-like cleavage may also occur with IRE1 and ATF6, two signaling molecules of the unfolded protein response (UPR) that may require PSs for their activation. Here, we have analyzed whether ATF6 cleavage requires a PS-dependent gamma -secretase activity and whether inhibition of gamma -secretase activity would affect the UPR. Endoproteolysis of ATF6 was observed in the presence of the highly potent y-secretase inhibitor L-685,458. ATF6 processing also occurred in the presence of functionally inactive dominant negative mutants of PSI(PS1 D385N) and PS2 (PS2 D366A) that do not support endoproteolysis of beta APP and Notch. Our results therefore demonstrate that ATF6 is not a substrate for PS mediated gamma -secretase-like endoproteolysis. This finding indicates that gamma -secretase inhibitors, which are currently developed as therapeutic agents to lower the A beta burden in brains of AD patients, do not interfere with the UPR response. (C) 2001 Academic Press.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/01/20 alle ore 21:59:29