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Nat Med. 2002 Sep;8(9):979-86. Epub 2002 Aug 19.

Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells.

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1
Cancer Immunology Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, Illinois, USA.

Abstract

Truncated Notch receptors have transforming activity in vitro and in vivo. However, the role of wild-type Notch signaling in neoplastic transformation remains unclear. Ras signaling is deregulated in a large fraction of human malignancies and is a major target for the development of novel cancer treatments. We show that oncogenic Ras activates Notch signaling and that wild-type Notch-1 is necessary to maintain the neoplastic phenotype in Ras-transformed human cells in vitro and in vivo. Oncogenic Ras increases levels and activity of the intracellular form of wild-type Notch-1, and upregulates Notch ligand Delta-1 and also presenilin-1, a protein involved in Notch processing, through a p38-mediated pathway. These observations place Notch signaling among key downstream effectors of oncogenic Ras and suggest that it might be a novel therapeutic target.

PMID:
12185362
DOI:
10.1038/nm754
[Indexed for MEDLINE]
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