Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenomatous Polyposis Coli Protein / genetics*
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Alleles
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Anaphase
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Animals
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Cell Proliferation
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Cell Survival
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Cells, Cultured
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Chromosome Aberrations
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Chromosome Banding
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Cytokinesis
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Cytoskeletal Proteins / metabolism
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Flow Cytometry
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Gene Expression Regulation, Developmental*
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Gene Rearrangement
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Genes, APC*
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Genotype
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Membrane Proteins / metabolism
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Metaphase
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Mice
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Mice, Transgenic
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Mitosis
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Models, Genetic
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Polymerase Chain Reaction
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Receptors, Antigen, T-Cell, alpha-beta / metabolism
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Receptors, Notch
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Recombination, Genetic
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Retroviridae / genetics
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Retroviridae / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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T-Lymphocytes / cytology*
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Thymus Gland / cytology*
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Thymus Gland / growth & development*
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Trans-Activators / metabolism
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VDJ Recombinases / metabolism
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beta Catenin
Substances
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Adenomatous Polyposis Coli Protein
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CTNNB1 protein, mouse
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Cytoskeletal Proteins
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Membrane Proteins
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Receptors, Antigen, T-Cell, alpha-beta
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Receptors, Notch
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Trans-Activators
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beta Catenin
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VDJ Recombinases