Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells.
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.
Weijzen
Sanne
S
Cancer Immunology Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, Illinois, USA.
Rizzo
Paola
P
Braid
Mike
M
Vaishnav
Radhika
R
Jonkheer
Suzanne M
SM
Zlobin
Andrei
A
Osborne
Barbara A
BA
Gottipati
Sridevi
S
Aster
Jon C
JC
Hahn
William C
WC
Rudolf
Michael
M
Siziopikou
Kalliopi
K
Kast
W Martin
WM
Miele
Lucio
L
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010641:Phenotype; D053764:Presenilin-1; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; C508853:PSEN1 protein, human; D053764:Presenilin-1; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors; C064045:delta protein; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins