共 49 条
Catalytic site-directed γ-secretase complex inhibitors do not discriminate pharmacologically between notch S3 and β-APP cleavages
被引:60
作者:

Lewis, HD
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机构: Merck Sharp & Dohme Res Labs, Neurosci Res Ctr, Dept Biochem & Mol Biol, Harlow CM20 2QR, Essex, England

Revuelta, BIP
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机构: Merck Sharp & Dohme Res Labs, Neurosci Res Ctr, Dept Biochem & Mol Biol, Harlow CM20 2QR, Essex, England

Nadin, A
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机构: Merck Sharp & Dohme Res Labs, Neurosci Res Ctr, Dept Biochem & Mol Biol, Harlow CM20 2QR, Essex, England

Neduvelil, JG
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机构: Merck Sharp & Dohme Res Labs, Neurosci Res Ctr, Dept Biochem & Mol Biol, Harlow CM20 2QR, Essex, England

Harrison, T
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机构: Merck Sharp & Dohme Res Labs, Neurosci Res Ctr, Dept Biochem & Mol Biol, Harlow CM20 2QR, Essex, England

Pollack, SJ
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机构: Merck Sharp & Dohme Res Labs, Neurosci Res Ctr, Dept Biochem & Mol Biol, Harlow CM20 2QR, Essex, England

Shearman, MS
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机构: Merck Sharp & Dohme Res Labs, Neurosci Res Ctr, Dept Biochem & Mol Biol, Harlow CM20 2QR, Essex, England
机构:
[1] Merck Sharp & Dohme Res Labs, Neurosci Res Ctr, Dept Biochem & Mol Biol, Harlow CM20 2QR, Essex, England
[2] Merck Sharp & Dohme Res Labs, Neurosci Res Ctr, Dept Med Chem, Harlow CM20 2QR, Essex, England
关键词:
D O I:
10.1021/bi034310g
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
The generation of gamma-secretase inhibitors which block the release of beta-amyloid peptide (Abeta) has long been an attractive therapeutic avenue for treatment or prevention of Alzheimer's disease (AD). Such inhibitors would reduce levels of Abeta available for aggregation into toxic assemblies that lead to the plaque pathology found in affected brain tissue. Cumulative evidence suggests that the S3 cleavage of Notch is also dependent on presenilins (PS) and is carried out by the multimeric PS-containing gamma-secretase complex. It is therefore possible that Notch function could be affected by gamma-secretase inhibitors. To assess the relationship between the cleavage of these substrates in the same system, Western blot cleavage assays have been established using a human cell line stably expressing both the beta-amyloid precursor protein (beta-APP) and the truncated Notch1 receptor fragment NotchDeltaE. Thus, a direct correlation may be made, following inhibitor treatment, of the decrease in the levels of the cleavage products, Abeta peptide and the Notch intracellular domain (NICD), as well as the increase in stabilized levels of both substrates. This analysis has been performed with a range of selected gamma-secretase inhibitors from six distinct structural classes. Changes in all four species usually occur in concert and with remarkably good agreement. A significant cleavage window is not clearly apparent in any case. Thus, these Notch and beta-APP cleavages cannot be dissected apart easily since they show the same pharmacological profile of inhibition. Whether this translates into proportionally reduced Notch signaling in vivo, however, remains to be seen.
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页码:7580 / 7586
页数:7
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Fuson, KS
论文数: 0 引用数: 0
h-index: 0
机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

Gitter, BD
论文数: 0 引用数: 0
h-index: 0
机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

Hyslop, PA
论文数: 0 引用数: 0
h-index: 0
机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

Johnstone, EM
论文数: 0 引用数: 0
h-index: 0
机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

Li, WY
论文数: 0 引用数: 0
h-index: 0
机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

Little, SP
论文数: 0 引用数: 0
h-index: 0
机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

Mabry, TE
论文数: 0 引用数: 0
h-index: 0
机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

Miller, FD
论文数: 0 引用数: 0
h-index: 0
机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

Ni, B
论文数: 0 引用数: 0
h-index: 0
机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA
[9]
Amyloid-lowering isocoumarins are not direct inhibitors of γ-secretase
[J].
Esler, WP
;
Das, C
;
Campbell, WA
;
Kimberly, WT
;
Kornilova, AY
;
Diehl, TS
;
Ye, WJ
;
Ostaszewski, BL
;
Xia, WM
;
Selkoe, DJ
;
Wolfe, MS
.
NATURE CELL BIOLOGY,
2002, 4 (05)
:E110-E111

Esler, WP
论文数: 0 引用数: 0
h-index: 0
机构: Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA

Das, C
论文数: 0 引用数: 0
h-index: 0
机构: Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA

Campbell, WA
论文数: 0 引用数: 0
h-index: 0
机构: Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA

Kimberly, WT
论文数: 0 引用数: 0
h-index: 0
机构: Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA

Kornilova, AY
论文数: 0 引用数: 0
h-index: 0
机构: Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA

Diehl, TS
论文数: 0 引用数: 0
h-index: 0
机构: Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA

Ye, WJ
论文数: 0 引用数: 0
h-index: 0
机构: Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA

Ostaszewski, BL
论文数: 0 引用数: 0
h-index: 0
机构: Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA

Xia, WM
论文数: 0 引用数: 0
h-index: 0
机构: Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA

Selkoe, DJ
论文数: 0 引用数: 0
h-index: 0
机构: Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA

Wolfe, MS
论文数: 0 引用数: 0
h-index: 0
机构: Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA
[10]
Activity-dependent isolation of the presenilin-γ-secretase complex reveals nicastrin and a γ substrate
[J].
Esler, WP
;
Kimberly, WT
;
Ostaszewski, BL
;
Ye, WJ
;
Diehl, TS
;
Selkoe, DJ
;
Wolfe, MS
.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,
2002, 99 (05)
:2720-2725

Esler, WP
论文数: 0 引用数: 0
h-index: 0
机构: Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA

Kimberly, WT
论文数: 0 引用数: 0
h-index: 0
机构: Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA

Ostaszewski, BL
论文数: 0 引用数: 0
h-index: 0
机构: Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA

Ye, WJ
论文数: 0 引用数: 0
h-index: 0
机构: Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA

Diehl, TS
论文数: 0 引用数: 0
h-index: 0
机构: Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA

Selkoe, DJ
论文数: 0 引用数: 0
h-index: 0
机构: Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA

Wolfe, MS
论文数: 0 引用数: 0
h-index: 0
机构: Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA