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.
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Change history
30 August 2002
This was incorrect in AOP version but corrected in print. Changed acknowledgements as per author's instructions.
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Acknowledgements
We thank T. Kadesch for the CBF-1 reporter plasmid; L. Heasley for the constitutively active MKK6 plasmid; B. Nickoloff for the dominant-negative mutant Ras construct; J.L. Bos for the constitutively active Rlf-CAAX plasmid; T. Golde for the γ-secretase inhibitor; and M.P. Velders, B. Nickoloff and V. Chaturvedi for helpful suggestions and critical reading of this manuscript. This work was supported by the Illinois Department of Public Health and NIH RO1 CA 84065/01 (to L.M.), NIH RO1 CA/AI 78399 (to W.M.K.), NIH RO1 A47922 (to B.A.O.), and a Doris Duke Charitable Fund Clinical Scientist Award (to W.C.H.).
NOTE: The acknowledgements originally published in the AOP version of this article were incorrect. The acknowledgements now appear correctly online, in both the full text and PDF versions of the article. The acknowledgements also appear correctly in the print version. The authors regret this error.
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Department of Adult Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Weijzen, S., Rizzo, P., Braid, M. et al. Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nat Med 8, 979–986 (2002). https://doi.org/10.1038/nm754
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DOI: https://doi.org/10.1038/nm754
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