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¹ Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
² Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
³ Laboratory of Molecular and Cellular Pathology, Hokkaido University Research Center for Zoonosis Control and 21st Century Center of Excellence Program for Zoonosis Control, Kita-ku, Sapporo 060-8638, Japan
⁴ Department of Immunology and Oncology, National Center for Biotechnology, Centro Nacional de Biotecnología, C/Darwin 3, 28049 Madrid, Spain
⁵ Department of Developmental Biology, Center for Translational and Advanced Animal Research, Graduate School of Medicine, Tohoku University, Aoba-ku, Sendai 980-8575, Japan

CORRESPONDENCE Keiichi I. Nakayama: nakayak1{at}bioreg.kyushu-u.ac.jp

Cell proliferation is strictly controlled during differentiation. In T cell development, the cell cycle is normally arrested at the CD4⁺CD8⁺ stage, but the mechanism underlying such differentiation-specific exit from the cell cycle has been unclear. Fbxw7 (also known as Fbw7, Sel-10, hCdc4, or hAgo), an F-box protein subunit of an SCF-type ubiquitin ligase complex, induces the degradation of positive regulators of the cell cycle, such as c-Myc, c-Jun, cyclin E, and Notch. FBXW7 is often mutated in a subset of human cancers. We have now achieved conditional inactivation of Fbxw7 in the T cell lineage of mice and found that the cell cycle is not arrested at the CD4⁺CD8⁺ stage in the homozygous mutant animals. The mutant mice manifested thymic hyperplasia as a result of c-Myc accumulation and eventually developed thymic lymphoma. In contrast, mature T cells of the mutant mice failed to proliferate in response to mitogenic stimulation and underwent apoptosis in association with accumulation of c-Myc and p53. These latter abnormalities were corrected by deletion of p53. Our results suggest that Fbxw7 regulates the cell cycle in a differentiation-dependent manner, with its loss resulting in c-Myc accumulation that leads to hyperproliferation in immature T cells but to p53-dependent cell-cycle arrest and apoptosis in mature T cells.

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