Conditional inactivation of Fbxw7 impairs cell-cycle exit during T cell differentiation and results in lymphomatogenesis.
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.
Onoyama
Ichiro
I
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
Tsunematsu
Ryosuke
R
Matsumoto
Akinobu
A
Kimura
Taichi
T
de Alborán
Ignacio Moreno
IM
Nakayama
Keiko
K
Nakayama
Keiichi I
KI
D000818:Animals; D000941:Antigens / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004198:Disease Susceptibility; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005786:Gene Expression Regulation / Q000187:drug effects; D019426:Integrases / Q000378:metabolism; D008223:Lymphoma / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*
D000941:Antigens; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513272:Fbxw7 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D051880:Receptors, Notch; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; C045073:Cre recombinase; D019426:Integrases