| Abstract: |
Background: Upon engagement of the T cell receptor for antigen, its associated CD3 proteins recruit signal transduction molecules, which in turn regulate T lymphocyte proliferation, apoptosis, and thymocyte development. Because some signal transducing molecules recruited by CD3-ε, i.e., p56(lck) and p59(fyn), are oncogenic and since we previously found that overexpression of CD3-ε transgenes causes a block in T lymphocyte and NK cell development, we tested the hypothesis that aberrant CD3-ε signaling leads both to abnormal T lymphocyte death and lymphomagenesis. Materials and Methods: Ten independently derived transgenic mouse lines were generated with four different genomic CD3-ε constructs. Mice either homozygous or hemizygous for each transgene were analyzed for an arrest in T lymphocyte development and for the occurrence of T cell lymphomas. Results: Aggressive clonal T cell lymphomas developed at very high frequencies in seven mouse lines with intermediate levels of copies of CD3-ε derived transgenes. However, these lymphomas were not found when high copy numbers of CD3-ε transgenes caused a complete block in early thymic development or when a transgene was used in which the exons coding for the CD3-ε protein were deleted. Analyses of a series of double mutant mice, tgCD3-ε x RAG-2(null), indicated that lymphomagenesis was initiated in lineage-committed prothymocytes, i.e., before rearrangement of the T cell receptor genes. In addition, the transgene coding for the CD3-ε cytoplasmic domain and its transmembrane region induced a T cell differentiation signal in premalignant tgCD3-ε x RAG-2(null) mice. Conclusion: The nonenzymatic CD3-ε protein acted as a potent oncogene when overexpressed early in T lymphocyte development. Lymphomagenesis was dependent on signal transduction events initiated by the cytoplasmic domain of CD3-ε. |
| Keywords: |
signal transduction; dna binding protein; genetics; dna-binding proteins; nonhuman; lymph nodes; cd3 antigen; antigen expression; lymphocyte proliferation; t lymphocyte; antigens, cd3; t-lymphocytes; proteins; mouse; animal; cytology; animals; mice; animal tissue; cell death; apoptosis; spleen; animal model; protein; pathology; protein tyrosine kinase; physiology; carcinogenesis; transgenic mouse; mice, transgenic; stem cell; oncogenes; growth, development and aging; oncogene; t lymphocyte receptor; t cell lymphoma; lymphoma, t-cell; thymus; thymus gland; lymph node; cytoplasm; thymoma; src-family kinases; thymocyte; protein kinase lck; thymus lymphoma; lymphocyte specific protein tyrosine kinase p56(lck); rag2 protein, mouse; priority journal; article; v(d)j recombination activating protein 2
|
