Identification of Protein Kinases Required for NF2 Signaling

Abstract

The purpose of this concept award grant is to uncover potential drug targets for treatment of Neurofibromatosis type 2 (NF2). We planned a synthetic lethal screen using RNAi technology to uncover protein kinases and phosphates that are specifically required for the survival of NF2-null cells. We also obtained and reformatted a murine siRNA library against all known protein kinases and phosphatases. We also obtained NF2flox/flox mouse embryo fibroblasts and used Cre recombinase to convert these to a NF24-genotype. We then tested a large number of transfection method worked well on the mouse embryo fibroblasts. We then obtained a library of bioactive chemicals and carried out a screen for synthetic lethality. This screen revealed that an inhibitor of the hedgehog pathway (cyclopamine) an inhibitor of Src-Family protein kinases (damnacanthal, as well as PP1 PP2 and tyrphostin) and an agonist of the constitutive androstane receptor (CITGO) all were selectively toxic to NF24-cells. These findings provided the basis for obtaining a grant from the Children's Tumor Foundation.

Open PDF

Document Details

Document Type
Technical Report
Publication Date
Dec 01, 2007
Accession Number
ADA494392

Entities

People

  • Jonathan Chernoff

Organizations

  • Fox Chase Cancer Center

Tags

DTIC Thesaurus Topics

  • Abstracts
  • Biomedical Research
  • Cells
  • Department Of Defense
  • Electronic Mail
  • Fibroblasts
  • Identification
  • Information Operations
  • Inhibitors
  • Lethality
  • Maryland
  • Molecules
  • Neoplasms
  • Small Molecules
  • Standards

Readers

  • Breast cancer cell signaling and growth regulation.
  • Molecular Biology and Genetics
  • Neurological Diseases/Conditions/Disorders