Oncogenic tyrosine kinases, DNA repair and survival: the role of Bcl-xL deamidation in transformation and genotoxic therapies.
Dysfunctional tyrosine kinases comprise an important class of oncogenes. We have generated a mouse model in which an oncogenic tyrosine kinase (OTK) causes T-lineage tumors. The model facilitates investigation of early oncogenic events in pretumorigenic thymocytes. The OTK transforms thymocytes by a 'double whammy' mechanism whereby on the one hand it inhibits DNA repair, leading to genomic instability, and on the other blocks DNA damage-induced apoptosis. The OTK-mediated blockade of apoptosis involves inhibition of DNA-damage triggered Bcl-xL deamidation, thereby preserving the protein's pro-survival functions. The pharmaceutical promotion of Bcl-xL deamidation might render cancer cells more sensitive to genotoxic attack.
Alexander
Denis R
DR
Laboratory of Lymphocyte Signaling and Development, Molecular Immunology Programme, The Babraham Institute, Cambridge, UK. denis.alexander@bbsrc.ac.uk
D000818:Animals; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D009857:Oncogenes; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism*; D013601:T-Lymphocytes / Q000502:physiology; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)