Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2005-06

AUTHORS

Johan H. van Es, Marielle E. van Gijn, Orbicia Riccio, Maaike van den Born, Marc Vooijs, Harry Begthel, Miranda Cozijnsen, Sylvie Robine, Doug J. Winton, Freddy Radtke, Hans Clevers

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. More... »

PAGES

959

Journal

TITLE

Nature

ISSUE

7044

VOLUME

435

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nature03659

    DOI

    http://dx.doi.org/10.1038/nature03659

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1046707660

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/15959515


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