Back
Full-text
Journal article

Coupling of mutated Met variants to DNA repair via Abl and Rad51.

Show more…
  • 2008-07-18
Published in:
  • Cancer research. - 2008
Active Transport, Cell Nucleus
Animals
Benzothiazoles
DNA Damage
DNA Repair
Genes, abl
Genetic Variation
Indoles
Mice
Mutation
NIH 3T3 Cells
Phosphorylation
Piperazines
Rad51 Recombinase
Radiation-Sensitizing Agents
Sulfonamides
Toluene
Tyrosine
English Abnormal activation of DNA repair pathways by deregulated signaling of receptor tyrosine kinase systems is a compelling likelihood with significant implications in both cancer biology and treatment. Here, we show that due to a potential substrate switch, mutated variants of the receptor for hepatocyte growth factor Met, but not the wild-type form of the receptor, directly couple to the Abl tyrosine kinase and the Rad51 recombinase, two key signaling elements of homologous recombination-based DNA repair. Treatment of cells that express the mutated receptor variants with the Met inhibitor SU11274 leads, in a mutant-dependent manner, to a reduction of tyrosine phosphorylated levels of Abl and Rad51, impairs radiation-induced nuclear translocation of Rad51, and acts as a radiosensitizer together with the p53 inhibitor pifithrin-alpha by increasing cellular double-strand DNA break levels following exposure to ionizing radiation. Finally, we propose that in order to overcome a mutation-dependent resistance to SU11274, this aberrant molecular axis may alternatively be targeted with the Abl inhibitor, nilotinib.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://sonar.ch/global/documents/1061
Statistics
Document views: 19 File downloads:
  • Full-text: 0