Conditional inactivation of Fbxw7 impairs cell-cycle exit during T cell differentiation and results in lymphomatogenesis
Conditional inactivation of Fbxw7 impairs cell-cycle exit during T cell differentiation and results in lymphomatogenesis
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DOI：
10.1084/jem.20062299
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发表时间：
2007-11-26
影响因子：
15.3
通讯作者：
Nakayama, Keiichi I.
中科院分区：
文献类型：
--
作者：
Onoyama, Ichiro;Tsunematsu, Ryosuke;Nakayama, Keiichi I.
细胞增殖在分化过程中受到严格控制。在T细胞发育中，细胞周期通常停滞在CD4(+)CD8(+)阶段，但这种分化特异性退出细胞周期的机制尚不清楚。 Fbxw7（也称为 Fbw7、Sel-10、hCdc4 或 hAgo）是 SCF 型泛素连接酶复合物的 F-box 蛋白亚基，可诱导细胞周期正调节因子（例如 c-Myc、c-Jun、cyclin E 和 Notch）的降解。 FBXW7 通常在一部分人类癌症中发生突变。我们现在已经在小鼠T细胞谱系中实现了Fbxw7的条件失活，并发现纯合突变动物的细胞周期并未停滞在CD4(+)CD8(+)阶段。突变小鼠由于c-Myc积累而表现出胸腺增生，并最终发展为胸腺淋巴瘤。相比之下，突变小鼠的成熟T细胞无法响应有丝分裂刺激而增殖，并随着c-Myc和p53的积累而发生凋亡。后面这些异常可通过删除 p53 来纠正。我们的结果表明，Fbxw7 以分化依赖性方式调节细胞周期，其缺失导致 c-Myc 积累，导致未成熟 T 细胞过度增殖，但在成熟 T 细胞中导致 p53 依赖性细胞周期停滞和凋亡。
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 hyper-proliferation in immature T cells but to p53-dependent cell-cycle arrest and apoptosis in mature T cells.