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  • Original Paper
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Ras pathway signals are required for notch-mediated oncogenesis

Oncogene volume 19, pages 4191–4198 (2000)Cite this article

Abstract

The Notch genes of C. elegans, Drosophila melanogaster and vertebrates encode receptors responsible for cell fate decisions during development. These Notch receptors and their ligands, Delta and Jagged, have been implicated in several human diseases. Truncated, constitutively active mutant forms of the Notch receptor appear to be involved in human T-cell leukemia, mammary carcinomas in mice, and a tumorous germline phenotype in C. elegans. Since activated Notch induces solitary tumors in transgenic mice, it is highly likely that collaborating genetic events are required for tumor formation. We have assessed four signal transduction pathways to determine which might play additional roles in malignant transformation in concert with activated Notch4. Our results suggest that transformation by Notch does not, as might have been expected, depend on the Src-like kinases Lck and Fyn, nor upon signals from protein kinase A and C (PKA, PKC). Rather, transformation by Notch requires active signals from the Erk/MAP kinase and PI-3 kinase pathways downstream of Ras.

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Acknowledgements

We thank Drs Laufey Amundadottir for advice on chemical treatment and soft agar assays, Robert Cardiff for pathology, Robert Callahan for MMTV-activated-Notch4, Lewis Cantley for DN-PI3 kinase, Juanita Torres and Dov Schwartz for cell cycle assistance. Susan Macdonald for Dn-Mek, David Dudley, Parke-Davis Pharmaceutical Research Division for UCN-01 and Drs Benedict Vollrath and Pamela Carroll for critical reading of this manuscript. K Fitzgerald was supported by a fellowship from the Leukemia Society of America during aspects of this work.

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  1. Kevin Fitzgerald

    Present address: Bristol Myers Squibb, 311 Pennington Rocky Hill, Building 3B, Pennington, 08534, New Jersey, NJ, USA

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  1. Department of Genetics, Harvard Medical School, Howard Hughes Medical Institute, 200 Longwood Avenue, Boston, 02115, Massachusetts, MA, USA

    Kevin Fitzgerald, Anne Harrington & Philip Leder

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Fitzgerald, K., Harrington, A. & Leder, P. Ras pathway signals are required for notch-mediated oncogenesis. Oncogene 19, 4191–4198 (2000). https://doi.org/10.1038/sj.onc.1203766

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