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Ras pathway signals are required for notch-mediated oncogenesis
K Fitzgerald1, A Harrington, P Leder
1Department of Genetics, Harvard Medical School, Howard Hughes Medical Institute, 200 Longwood Avenue, Boston, Massachusetts, MA 02115, USA.
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. Oncogene (2000) 19, 4191 - 4198
Insights
Activated Notch signaling contributes to cancer by requiring Erk/MAP kinase and PI-3 kinase pathways. These pathways are essential for malignant transformation, not Src-like kinases or PKA/PKC signals.
Area of Science:
- Cell biology
- Developmental biology
- Cancer research
Background:
- Notch receptors and ligands (Delta, Jagged) regulate cell fate during development.
- Mutant Notch receptors are implicated in human T-cell leukemia and mouse mammary carcinomas.
- Activated Notch signaling can induce tumors, suggesting collaboration with other genetic events.
Purpose of the Study:
- To investigate which signal transduction pathways cooperate with activated Notch4 in malignant transformation.
- To identify key signaling pathways involved in Notch-induced tumorigenesis.
Main Methods:
- Assessment of four distinct signal transduction pathways.
- Analysis of the role of Src-like kinases (Lck, Fyn), protein kinase A (PKA), and protein kinase C (PKC).
- Evaluation of the involvement of Erk/MAP kinase and PI-3 kinase pathways downstream of Ras.
Main Results:
- Malignant transformation by Notch did not depend on Lck, Fyn, PKA, or PKC signaling.
- Active signals from Erk/MAP kinase and PI-3 kinase pathways downstream of Ras are required for Notch-induced transformation.
- These findings highlight specific pathways crucial for Notch-mediated oncogenesis.
Conclusions:
- Erk/MAP kinase and PI-3 kinase pathways are essential collaborators in Notch-driven malignant transformation.
- The study elucidates key downstream effectors of Ras signaling in Notch-induced cancer.
- Understanding these pathways offers potential targets for cancer therapy.