Rapid Notch1 nuclear translocation after ligand binding depends on presenilin-associated γ-secretase activity

Oksana Berezovska, Christine Jack, Pamela J McLean, Jon C. Aster, Carol Hicks, X. I A Weiming, Michael S. Wolfe, Gerry Weinmaster, Dennis J. Selkoe, Bradley T. Hyman

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Recent data suggest an intimate relationship between the familial Alzheimer disease gene presenilin 1 (PS1) and proteolytic processing of both the amyloid precursor protein (APP) and the important cell signaling molecule, Notch1. We now show, using mammalian cells transfected with full-length Notch1, that the C terminal domain of Notch1 rapidly translocates to the nucleus upon stimulation with the physiologic ligand Delta and initiates a CBF1-dependent signal transduction cascade. Using this assay, we demonstrate that the same aspartate mutations in PS1 that block APP processing also prevent Notch1 cleavage and translocation to the nucleus. Moreover, we show that two APP γ-secretase inhibitors also diminish Notch1 nuclear translocation in a dose-dependent fashion. However, Notch1 signaling, assessed by measuring the activity of CBF1, a downstream gene, was reduced but not completely abolished in the presence of either aspartate mutations or γ-secretase inhibitors. Our results support the hypothesis that similar PS1-related enzymatic activity is necessary for both APP and Notch1 processing, yet suggest that Notch signaling may remain relatively preserved with moderate levels of γ-secretase inhibition.

Original languageEnglish (US)
Pages (from-to)223-226
Number of pages4
JournalAnnals of the New York Academy of Sciences
Volume920
StatePublished - 2000
Externally publishedYes

Fingerprint

Presenilins
Presenilin-1
Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor
Ligands
Aspartic Acid
Processing
Genes
Cell signaling
Signal transduction
Mutation
Assays
Signal Transduction
Alzheimer Disease
Cells
Molecules
Translocation
Protein
Precursor
Gene

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Berezovska, O., Jack, C., McLean, P. J., Aster, J. C., Hicks, C., Weiming, X. I. A., ... Hyman, B. T. (2000). Rapid Notch1 nuclear translocation after ligand binding depends on presenilin-associated γ-secretase activity. Annals of the New York Academy of Sciences, 920, 223-226.

Rapid Notch1 nuclear translocation after ligand binding depends on presenilin-associated γ-secretase activity. / Berezovska, Oksana; Jack, Christine; McLean, Pamela J; Aster, Jon C.; Hicks, Carol; Weiming, X. I A; Wolfe, Michael S.; Weinmaster, Gerry; Selkoe, Dennis J.; Hyman, Bradley T.

In: Annals of the New York Academy of Sciences, Vol. 920, 2000, p. 223-226.

Research output: Contribution to journalArticle

Berezovska, O, Jack, C, McLean, PJ, Aster, JC, Hicks, C, Weiming, XIA, Wolfe, MS, Weinmaster, G, Selkoe, DJ & Hyman, BT 2000, 'Rapid Notch1 nuclear translocation after ligand binding depends on presenilin-associated γ-secretase activity', Annals of the New York Academy of Sciences, vol. 920, pp. 223-226.
Berezovska, Oksana ; Jack, Christine ; McLean, Pamela J ; Aster, Jon C. ; Hicks, Carol ; Weiming, X. I A ; Wolfe, Michael S. ; Weinmaster, Gerry ; Selkoe, Dennis J. ; Hyman, Bradley T. / Rapid Notch1 nuclear translocation after ligand binding depends on presenilin-associated γ-secretase activity. In: Annals of the New York Academy of Sciences. 2000 ; Vol. 920. pp. 223-226.
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