Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL
Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL
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DOI：
10.1101/gad.1621808
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发表时间：
2008-04-15
影响因子：
10.5
通讯作者：
Suda, Toshio
中科院分区：
文献类型：
--
作者：
Matsuoka, Sahoko;Oike, Yuichi;Suda, Toshio
造血干细胞(HSC)维持和白血病预防之间的共同分子机制已被强调。肿瘤抑制因子Fbxw7(F-box和WD-40结构域蛋白7)是SCF型泛素连接酶复合体的一个亚单位，可诱导细胞周期正调控因子的降解。我们证明，在造血细胞中，Fbxw7的失活会由于活跃的细胞周期和依赖于P53的细胞凋亡而导致HSCs过早耗尽。有趣的是，Fbxw7的缺失也为p53功能受抑制的细胞提供了选择性优势，最终导致T细胞急性淋巴细胞白血病(T-ALL)的发生。因此，Fbxw7作为一种故障安全机制，既可以防止过早的HSC丢失，也可以防止白血病的发生。
Common molecular machineries between hematopoietic stem cell (HSC) maintenance and leukemia prevention have been highlighted. The tumor suppressor Fbxw7 (F-box and WD-40 domain protein 7), a subunit of an SCF-type ubiquitin ligase complex, induces the degradation of positive regulators of the cell cycle. We demonstrate that inactivation of Fbxw7 in hematopoietic cells causes premature depletion of HSCs due to active cell cycling and p53-dependent apoptosis. Interestingly, Fbxw7 deletion also confers a selective advantage to cells with suppressed p53 function, eventually leading to development of T-cell acute lymphoblastic leukemia (T-ALL). Thus, Fbxw7 functions as a fail-safe mechanism against both premature HSC loss and leukemogenesis.