Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells

Details

Serval ID
serval:BIB_3255FC3F85CA
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells
Journal
Nature
Author(s)
van Es  J. H., van Gijn  M. E., Riccio  O., van den Born  M., Vooijs  M., Begthel  H., Cozijnsen  M., Robine  S., Winton  D. J., Radtke  F., Clevers  H.
ISSN
1476-4687 (Electronic)
Publication state
Published
Issued date
06/2005
Volume
435
Number
7044
Pages
959-63
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Jun 16
Abstract
The self-renewing epithelium of the small intestine is ordered into stem/progenitor crypt compartments and differentiated villus compartments. Recent evidence indicates that the Wnt cascade is the dominant force in controlling cell fate along the crypt-villus axis. Here we show a rapid, massive conversion of proliferative crypt cells into post-mitotic goblet cells after conditional removal of the common Notch pathway transcription factor CSL/RBP-J. We obtained a similar phenotype by blocking the Notch cascade with a gamma-secretase inhibitor. The inhibitor also induced goblet cell differentiation in adenomas in mice carrying a mutation of the Apc tumour suppressor gene. Thus, maintenance of undifferentiated, proliferative cells in crypts and adenomas requires the concerted activation of the Notch and Wnt cascades. Our data indicate that gamma-secretase inhibitors, developed for Alzheimer's disease, might be of therapeutic benefit in colorectal neoplastic disease.
Keywords
Adenoma/enzymology/genetics/metabolism/*pathology Amyloid Precursor Protein Secretases Animals Aspartic Endopeptidases Cell Differentiation/drug effects Cell Proliferation/*drug effects DNA-Binding Proteins/deficiency/genetics/metabolism Dibenzazepines/pharmacology Endopeptidases/*metabolism Female Genes, APC Goblet Cells/*cytology/drug effects/metabolism/pathology Immunoglobulin J Recombination Signal Sequence-Binding Protein Intestine, Small/*cytology/drug effects/enzymology/metabolism Male Membrane Proteins/*antagonists & inhibitors/metabolism Mice Mice, Inbred C57BL Nuclear Proteins/deficiency/genetics/metabolism Phenotype Protease Inhibitors/*pharmacology Receptors, Notch Signal Transduction/drug effects
Pubmed
Web of science
Create date
28/01/2008 11:39
Last modification date
20/08/2019 13:17
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