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

• Published in: Nature medicine Vol. 8; no. 9; pp. 979 - 986
• Main Authors: Miele, Lucio, Weijzen, Sanne, Rizzo, Paola, Braid, Mike, Vaishnav, Radhika, Jonkheer, Suzanne M, Zlobin, Andrei, Osborne, Barbara A, Gottipati, Sridevi, Aster, Jon C, Hahn, William C, Rudolf, Michael, Siziopikou, Kalliopi, Kast, W. Martin
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.09.2002
• Subjects: Animals; Antimitotic agents; Antineoplastic agents; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cancer; Cell Transformation, Neoplastic - genetics; Cells; Cells, Cultured; Down-Regulation; Female; Fibroblasts; Gene Expression Regulation, Neoplastic - genetics; Genetic aspects; Genotype & phenotype; Health aspects; Humans; Intracellular Signaling Peptides and Proteins; Ligands; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, SCID; Mitogen-Activated Protein Kinases - metabolism; p38 Mitogen-Activated Protein Kinases; Phenotype; Presenilin-1; Proteins; ras Proteins - genetics; ras Proteins - metabolism; Receptor, Notch1; Receptors, Cell Surface; Signal Transduction - genetics; Transcription Factors; Up-Regulation; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - metabolism; United States > US; Massachusetts; Illinois
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm754

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.