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

Sanne Weijzen, Paola Rizzo, Mike Braid, Radhika Vaishnav, Suzanne M. Jonkheer, Andrei Zlobin, Barbara A. Osborne, Sridevi Gottipati, Jon C. Aster, William C. Hahn, Michael Rudolf, Kalliopi Siziopikou, W. Martin Kast, Lucio Miele

Research output: Contribution to journalArticlepeer-review

462 Scopus citations

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 wildtype 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 wildtype 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.

Original languageEnglish (US)
Pages (from-to)979-986
Number of pages8
JournalNature Medicine
Volume8
Issue number9
DOIs
StatePublished - Sep 2002

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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