An oncogenic tyrosine kinase inhibits DNA repair and DNA-damage-induced Bcl-xL deamidation in T cell transformation

Cancer Cell. 2004 Jan;5(1):37-49. doi: 10.1016/s1535-6108(03)00333-7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle / physiology
  • Cells, Cultured
  • Chromosomal Instability / physiology
  • DNA Damage / drug effects
  • DNA Damage / physiology
  • DNA Repair / drug effects
  • DNA Repair / physiology
  • Karyotyping
  • Leukemia, T-Cell / physiopathology*
  • Leukocyte Common Antigens / genetics
  • Leukocyte Common Antigens / metabolism
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / genetics
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism*
  • Mice
  • Mice, Transgenic
  • Models, Animal
  • Neoplasms, Experimental / physiopathology
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Signal Transduction
  • T-Lymphocytes / cytology
  • T-Lymphocytes / metabolism
  • Up-Regulation / physiology
  • bcl-X Protein


  • Bcl2l1 protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-X Protein
  • Protein-Tyrosine Kinases
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • Leukocyte Common Antigens