Abstract
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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Cycle / physiology
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Cells, Cultured
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Chromosomal Instability / physiology
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DNA Damage / drug effects
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DNA Damage / physiology
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DNA Repair / drug effects
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DNA Repair / physiology
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Karyotyping
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Leukemia, T-Cell / physiopathology*
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Leukocyte Common Antigens / genetics
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Leukocyte Common Antigens / metabolism
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / genetics
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism*
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Mice
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Mice, Transgenic
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Models, Animal
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Neoplasms, Experimental / physiopathology
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Phosphorylation
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Signal Transduction
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T-Lymphocytes / cytology
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T-Lymphocytes / metabolism
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Up-Regulation / physiology
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bcl-X Protein
Substances
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Bcl2l1 protein, mouse
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Proto-Oncogene Proteins c-bcl-2
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bcl-X Protein
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Protein-Tyrosine Kinases
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
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Leukocyte Common Antigens