Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy
Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy
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DOI：
10.1038/onc.2008.77
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发表时间：
2008-07-24
期刊：
影响因子：
8
通讯作者：
Shaulian, E.
中科院分区：
文献类型：
--
作者：
Finkin, S.;Aylon, Y.;Shaulian, E.
Fbw7是一种肿瘤抑制因子，在许多癌症中发生突变。它编码E3泛素连接酶，其降低细胞生长和增殖的关键调节因子水平的能力是其肿瘤抑制功能的基础。在这里，我们探讨Fbw7失活对化疗治疗结果的影响。当暴露于纺锤体毒素如长春碱和紫杉醇时，Fbw7缺陷细胞经历广泛的有丝分裂滑移和核内复制，使其成为多倍体。这种表型需要几种Fbw7靶蛋白的组合失调。具体来说，Fbw 7缺陷细胞中细胞周期蛋白E和Aurora A的表达升高是药物诱导的多倍化所必需的。然而，单独的细胞周期蛋白E或极光A的过度表达不足以产生药物诱导的多倍体。此外，我们证明Fbw7缺陷限制了p53对有丝分裂毒素的反应能力，但对DNA损伤没有影响。此外，Fbw7表达调节p53依赖性诱导基因，如Lats2和p21响应长春碱。因此，我们认为Fbw7作为一个主调节器的有丝分裂和四倍体检查点。
Fbw7 is a tumor suppressor that is mutated in numerous cancers. It encodes an E3 ubiquitin ligase, whose ability to decrease the levels of pivotal regulators of cell growth and proliferation underlies its tumor suppressor function. Here, we explore the consequences of Fbw7 inactivation on the outcome of chemotherapeutic treatments. When exposed to spindle toxins such as vinblastine and taxol, Fbw7-deficient cells undergo extensive mitotic slippage and endoreduplication, rendering them polyploid. A combined deregulation of several Fbw7 target proteins is required for this phenotype. Specifically, elevated expression of cyclin E and Aurora A in Fbw7-deficient cells is required for drug-induced polyploidy. However, overexpression of either cyclin E or Aurora A alone is not sufficient for drug-induced polyploidy. In addition, we demonstrate that Fbw7 deficiency limits the ability of p53 to respond to mitotic toxins but not to DNA damage. Furthermore, Fbw7 expression regulates the p53-dependent induction of genes such as Lats2 and p21 in response to vinblastine. Hence, we suggest that Fbw7 serves as a master regulator of the mitotic and tetraploidy checkpoints.