Conditional inactivation of Fbxw7 impairs cell-cycle exit during T cell differentiation and results in lymphomatogenesis

Ichiro Onoyama, Ryosuke Tsunematsu, Akinobu Matsumoto, Taichi Kimura, Ignacio Moreno De Alborán, Keiko Nakayama, Keiichi I. Nakayama

Research output: Contribution to journalArticle

144 Citations (Scopus)

Abstract

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. JEM

Original languageEnglish
Pages (from-to)2875-2888
Number of pages14
JournalJournal of Experimental Medicine
Volume204
Issue number12
DOIs
Publication statusPublished - Nov 26 2007

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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