{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T14:19:03Z","timestamp":1791037143179,"version":"4.1.0"},"reference-count":53,"publisher":"Rockefeller University Press","issue":"12","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2007,11,26]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1084\/jem.20062299","type":"journal-article","created":{"date-parts":[[2007,11,6]],"date-time":"2007-11-06T01:53:49Z","timestamp":1194314029000},"page":"2875-2888","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":166,"title":["Conditional inactivation of <i>Fbxw7<\/i> impairs cell-cycle exit during T cell differentiation and results in lymphomatogenesis"],"prefix":"10.1084","volume":"204","author":[{"given":"Ichiro","family":"Onoyama","sequence":"first","affiliation":[{"name":"1Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan"},{"name":"2Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryosuke","family":"Tsunematsu","sequence":"additional","affiliation":[{"name":"1Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan"},{"name":"2Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akinobu","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"1Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan"},{"name":"2Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taichi","family":"Kimura","sequence":"additional","affiliation":[{"name":"3Laboratory 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio Moreno","family":"de Albora\u0301n","sequence":"additional","affiliation":[{"name":"4Department of Immunology and Oncology, National Center for Biotechnology, Centro Nacional de Biotecnologi\u0301a, C\/Darwin 3, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Nakayama","sequence":"additional","affiliation":[{"name":"2Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan"},{"name":"5Department of Developmental Biology, Center for Translational and Advanced Animal Research, Graduate School of Medicine, Tohoku University, Aoba-ku, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiichi I.","family":"Nakayama","sequence":"additional","affiliation":[{"name":"1Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan"},{"name":"2Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2007,11,5]]},"reference":[{"key":"2023072515245580800_BIB1","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/S0092-8674(00)80563-2","volume":"96","year":"1999","journal-title":"Cell."},{"key":"2023072515245580800_BIB2","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1002\/j.1460-2075.1991.tb07929.x","volume":"10","year":"1991","journal-title":"EMBO J."},{"key":"2023072515245580800_BIB3","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/S0959-437X(05)80278-3","volume":"2","year":"1992","journal-title":"Curr. 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