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 β-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) β, encouraging developmental progression of aberrant thymocytes lacking pre-TCR and αβ 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 β-catenin signaling and is essential for T cell differentiation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 800-809 |
| Number of pages | 10 |
| Journal | Nature Immunology |
| Volume | 6 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 2005 |
Funding
The authors thank J.C. Zúñiga-Pflücker (University of Toronto, Toronto, Canada) for advice, support and the OP9-DL1 cells; I. Khan for help with the OP9-DL1 cultures; K. Georgopoulos (Massachusetts General Hospital), P. Sicinski and R. Van Etten for critical comments on the manuscript; I. Aifantis (University of Chicago), X. Li and A. Campese for the NotchIC retrovirus; and H. von Boehmer and R.M. Meyer for their interest and support. Supported by the National Institutes of Health (R01 AI059676-01 to F.G. and R01 CA104547-01A1 to K.K.), the Medical Foundation (Smith Family New Investigator Award to F.G.), the Dana Farber Cancer Institute (National Colorectal Cancer Research Alliance Award to K.K.) and the Claudia Adams Barr Program (K.K.).
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
