Tumor Suppressor VHL Functions in the Control of Mitotic Fidelity
Tumor Suppressor VHL Functions in the Control of Mitotic Fidelity
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DOI：
10.1158/0008-5472.can-13-2040
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发表时间：
2014-05-01
期刊：
影响因子：
11.2
通讯作者：
Krek, Wilhelm
中科院分区：
文献类型：
--
作者：
Hell, Michael P.;Duda, Maria;Krek, Wilhelm
Von Hippel-Lindau(VHL)抑癌蛋白pVHL在肾透明细胞癌(CcRCC)中常见突变，参与调控多种细胞过程，可能与肿瘤抑制有关，包括促进正确的纺锤体取向和染色体稳定性。然而，目前还不清楚pVHL是否也在体内发挥这些有丝分裂调节功能。在这里，我们应用了缺血肾损伤来刺激细胞分裂，否则静止的小鼠成年肾脏。我们发现在短期内(手术后5.5天)，VHL缺陷的肾细胞既表现为纺锤体定向错误，也表现为非整倍体。纺锤体定向错误表型包括定向细胞分裂的变化，这可能在囊性病变的发展中表现出来，而非整倍体表型涉及落后染色体的出现，但没有染色体桥，这表明有丝分裂检查点损伤。有趣的是，从长期来看(缺血性损伤后4个月)，VHL缺陷的肾脏表现出ccRCC前体病变的异质性模式，包括囊性病变、透明细胞型细胞和异型增生。综上所述，这些数据为pVHL在介导肾上皮定向细胞分裂和忠实的有丝分裂检查点功能中的关键作用提供了直接证据，强调了pVHL作为体内有丝分裂保真度控制器的重要性。(C)2013年AACR。
The von Hippel-Lindau (VHL) tumor suppressor protein pVHL is commonly mutated in clear cell renal cell carcinoma (ccRCC) and has been implicated in the control of multiple cellular processes that might be linked to tumor suppression, including promoting proper spindle orientation and chromosomal stability. However, it is unclear whether pVHL exerts these mitotic regulatory functions in vivo as well. Here, we applied ischemic kidney injury to stimulate cell division in otherwise quiescent mouse adult kidneys. We show that in the short term (5.5 days after surgery), Vhl-deficient kidney cells demonstrate both spindle misorientation and aneuploidy. The spindle misorientation phenotype encompassed changes in directed cell division, which may manifest in the development of cystic lesions, whereas the aneuploidy phenotype involved the occurrence of lagging chromosomes but not chromosome bridges, indicative of mitotic checkpoint impairment. Intriguingly, in the long term (4 months after the ischemic insult), Vhl-deficient kidneys displayed a heterogeneous pattern of ccRCC precursor lesions, including cysts, clear cell-type cells, and dysplasia. Together, these data provide direct evidence for a key role of pVHL in mediating oriented cell division and faithful mitotic checkpoint function in the renal epithelium, emphasizing the importance of pVHL as a controller of mitotic fidelity in vivo. (C) 2013 AACR.