An oncogenic tyrosine kinase inhibits DNA repair and DNA-damage-induced Bcl-xL deamidation in T cell transformation.
A transgenic mouse model of T cell lymphoma was used to investigate the transforming events mediated by an oncogenic tyrosine kinase in pretumorigenic CD4-CD8- (DN) thymocytes. Parental CD45(-/-) and p56(lck-F505Y) mice do not develop tumors, whereas their CD45(-/-)p56(lck-F505Y) progeny develop T lymphomas. Increased but nononcogenic p56lck kinase activity in p56(lck-F505Y) mice DN thymocytes causes cell-cycle progression, survival, and Bcl-XL upregulation. Additional unique oncogenic signals occur in pretumorigenic CD45(-/-)p56(lck-F505Y) thymocytes in which p56lck kinase activity is 2- to 3-fold higher relative to p56(lck-F505Y): inhibition of DNA repair, inhibition of DNA-damage-induced Bcl-XL deamidation, Bax conformational change and mitochondrial translocation, cytochrome c release, and the apoptotic caspase execution cascade. Inhibition of Bcl-XL deamidation may be a critical switch in oncogenic kinase-induced T cell transformation.
Zhao
Rui
R
Laboratory of Lymphocyte Signalling and Development, Molecular Immunology Programme, The Babraham Institute, Babraham, Cambridge CB2 4AT, UK.
Yang
Feng Tang
FT
Alexander
Denis R
DR
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D002478:Cells, Cultured; D043171:Chromosomal Instability / Q000502:physiology; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology; D007621:Karyotyping; D015458:Leukemia, T-Cell / Q000503:physiopathology*; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000378:metabolism; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009374:Neoplasms, Experimental / Q000503:physiopathology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D017493:Leukocyte Common Antigens