Activation of Notch-1 Signaling Maintains the Neoplastic Phenotype in Human Ras-transformed Cells

Nat Med. 2002 Sep;8(9):979-86. doi: 10.1038/nm754. Epub 2002 Aug 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Cell Transformation, Neoplastic / genetics*
  • Cells, Cultured
  • Down-Regulation
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, SCID
  • Mitogen-Activated Protein Kinases / metabolism
  • Phenotype
  • Presenilin-1
  • Receptor, Notch1
  • Receptors, Cell Surface*
  • Signal Transduction / genetics*
  • Transcription Factors*
  • Up-Regulation
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / metabolism
  • p38 Mitogen-Activated Protein Kinases
  • ras Proteins / genetics
  • ras Proteins / metabolism*

Substances

  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NOTCH1 protein, human
  • Notch1 protein, mouse
  • PSEN1 protein, human
  • Presenilin-1
  • Receptor, Notch1
  • Receptors, Cell Surface
  • Transcription Factors
  • delta protein
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • ras Proteins