Ras Pathway Signals Are Required for Notch-Mediated Oncogenesis

Oncogene. 2000 Aug 31;19(37):4191-8. doi: 10.1038/sj.onc.1203766.

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

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans Proteins*
  • Cell Transformation, Neoplastic* / genetics
  • Helminth Proteins / physiology
  • Hematoma / etiology
  • Humans
  • MAP Kinase Signaling System / physiology
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / pathology
  • Membrane Proteins / physiology
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinase 1 / physiology
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase Kinases / physiology
  • Mitogen-Activated Protein Kinases / physiology
  • Neoplasm Transplantation
  • Oncogene Protein p21(ras) / physiology
  • Phosphatidylinositol 3-Kinases / physiology
  • Protein-Serine-Threonine Kinases*
  • Protein-Tyrosine Kinases / physiology
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-akt
  • Receptor, Notch4
  • Receptors, Cell Surface*
  • Receptors, Notch
  • Recombinant Fusion Proteins / biosynthesis
  • Salivary Gland Neoplasms / genetics
  • Salivary Gland Neoplasms / pathology
  • Signal Transduction / physiology*
  • Transfection
  • Tumor Cells, Cultured
  • ras Proteins / physiology*

Substances

  • Caenorhabditis elegans Proteins
  • Helminth Proteins
  • Lin-12 protein, C elegans
  • Membrane Proteins
  • NOTCH4 protein, human
  • Proto-Oncogene Proteins
  • Receptor, Notch4
  • Receptors, Cell Surface
  • Receptors, Notch
  • Recombinant Fusion Proteins
  • Phosphatidylinositol 3-Kinases
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • Oncogene Protein p21(ras)
  • ras Proteins