PMID- 10206645
OWN - NLM
STAT- MEDLINE
DCOM- 19990428
LR  - 20091119
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 398
IP  - 6727
DP  - 1999 Apr 8
TI  - A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch 
      intracellular domain.
PG  - 518-22
AB  - Signalling through the receptor protein Notch, which is involved in crucial
      cell-fate decisions during development, requires ligand-induced cleavage of
      Notch. This cleavage occurs within the predicted transmembrane domain, releasing 
      the Notch intracellular domain (NICD), and is reminiscent of
      gamma-secretase-mediated cleavage of beta-amyloid precursor protein (APP), a
      critical event in the pathogenesis of Alzheimer's disease. A deficiency in
      presenilin-1 (PS1) inhibits processing of APP by gamma-secretase in mammalian
      cells, and genetic interactions between Notch and PS1 homologues in
      Caenorhabditis elegans indicate that the presenilins may modulate the Notch
      signalling pathway. Here we report that, in mammalian cells, PS1 deficiency also 
      reduces the proteolytic release of NICD from a truncated Notch construct, thus
      identifying the specific biochemical step of the Notch signalling pathway that is
      affected by PS1. Moreover, several gamma-secretase inhibitors block this same
      step in Notch processing, indicating that related protease activities are
      responsible for cleavage within the predicted transmembrane domains of Notch and 
      APP. Thus the targeting of gamma-secretase for the treatment of Alzheimer's
      disease may risk toxicity caused by reduced Notch signalling.
FAU - De Strooper, B
AU  - De Strooper B
AD  - Neuronal Cell Biology and Gene Transfer Laboratory, Flanders Institute for
      Biotechnology (VIB4), Center for Human Genetics, KU Leuven, Belgium.
      Bart.Destrooper@med.kuleuven.ac.be
FAU - Annaert, W
AU  - Annaert W
FAU - Cupers, P
AU  - Cupers P
FAU - Saftig, P
AU  - Saftig P
FAU - Craessaerts, K
AU  - Craessaerts K
FAU - Mumm, J S
AU  - Mumm JS
FAU - Schroeter, E H
AU  - Schroeter EH
FAU - Schrijvers, V
AU  - Schrijvers V
FAU - Wolfe, M S
AU  - Wolfe MS
FAU - Ray, W J
AU  - Ray WJ
FAU - Goate, A
AU  - Goate A
FAU - Kopan, R
AU  - Kopan R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (CCAAT-Enhancer-Binding Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Peptide Fragments)
RN  - 0 (Presenilin-1)
RN  - 0 (Receptors, Notch)
RN  - 0 (Srebf1 protein, mouse)
RN  - 0 (Sterol Regulatory Element Binding Protein 1)
RN  - 0 (Transcription Factors)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
RN  - EC 3.4.- (Endopeptidases)
RN  - EC 3.4.23.- (Aspartic Acid Endopeptidases)
RN  - EC 3.4.23.46 (Bace1 protein, mouse)
SB  - IM
CIN - Nature. 1999 Apr 8;398(6727):466-7. PMID: 10206639
MH  - Alzheimer Disease/drug therapy
MH  - Amyloid Precursor Protein Secretases
MH  - Amyloid beta-Protein Precursor/metabolism
MH  - Animals
MH  - Aspartic Acid Endopeptidases
MH  - Brain/metabolism
MH  - *CCAAT-Enhancer-Binding Proteins
MH  - Cells, Cultured
MH  - Cytoplasm/metabolism
MH  - DNA-Binding Proteins/metabolism
MH  - Endopeptidases/*metabolism
MH  - Fibroblasts/metabolism
MH  - Membrane Proteins/*metabolism
MH  - Mice
MH  - Neurons/metabolism
MH  - Nuclear Proteins/metabolism
MH  - Peptide Fragments/metabolism
MH  - Presenilin-1
MH  - Protein Processing, Post-Translational
MH  - Receptors, Notch
MH  - *Signal Transduction
MH  - Sterol Regulatory Element Binding Protein 1
MH  - *Transcription Factors
EDAT- 1999/04/17 02:16
MHDA- 2001/03/23 10:01
CRDT- 1999/04/17 02:16
PHST- 1999/04/17 02:16 [pubmed]
PHST- 2001/03/23 10:01 [medline]
PHST- 1999/04/17 02:16 [entrez]
AID - 10.1038/19083 [doi]
PST - ppublish
SO  - Nature. 1999 Apr 8;398(6727):518-22. doi: 10.1038/19083.