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Loss of adenomatous polyposis coli gene function disrupts thymic development.

Nature immunology | Aug 21, 2005

Loss of the adenomatous polyposis coli (APC) protein is a common initiating event in colon cancer. Here we show that thymocyte-specific loss of APC deregulated beta-catenin signaling and suppressed Notch-dependent transcription. These events promoted the proliferation of cells of the double-negative 3 and 4 stages and reduced rearrangements between the variable, diversity and joining regions of the gene encoding T cell receptor (TCR) beta, encouraging developmental progression of aberrant thymocytes lacking pre-TCR and alphabeta TCR. Simultaneously, the loss of APC prolonged the mitotic metaphase-to-anaphase checkpoint and impaired chromosome segregation, blocking development beyond the double-negative 4 stage. The result was extensive thymic atrophy and increased frequencies of thymocytes with chromosomal abnormalities. Thus, loss of APC in immature thymocytes has consequences distinct from those of deregulation of beta-catenin signaling and is essential for T cell differentiation.

Pubmed ID: 16025118 RIS Download

Mesh terms: Adenomatous Polyposis Coli Protein | Alleles | Anaphase | Animals | Cell Proliferation | Cell Survival | Cells, Cultured | Chromosome Aberrations | Chromosome Banding | Cytokinesis | Cytoskeletal Proteins | Flow Cytometry | Gene Expression Regulation, Developmental | Gene Rearrangement | Genes, APC | Genotype | Membrane Proteins | Metaphase | Mice | Mice, Transgenic | Mitosis | Models, Genetic | Polymerase Chain Reaction | Receptors, Antigen, T-Cell, alpha-beta | Receptors, Notch | Recombination, Genetic | Retroviridae | Reverse Transcriptase Polymerase Chain Reaction | Signal Transduction | T-Lymphocytes | Thymus Gland | Trans-Activators | VDJ Recombinases | beta Catenin

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Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA104547
  • Agency: NCI NIH HHS, Id: R01 CA104547-01A1
  • Agency: NIAID NIH HHS, Id: R01 AI059676-02
  • Agency: NIAID NIH HHS, Id: R01 AI059676-01
  • Agency: NIAID NIH HHS, Id: R01 AI059676

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