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Ischemic renal injury reveals in vivo functions for the von Hippel-Lindau tumor suppressor in mitotic fidelity control


Hell, Michael P; Duda, Maria; Weber, Thomas C; Moch, Holger; Krek, Wilhelm (2013). Ischemic renal injury reveals in vivo functions for the von Hippel-Lindau tumor suppressor in mitotic fidelity control. Cancer Research:1-32.

Abstract

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 also in vivo. 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 post 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, while the aneuploidy phenotype involved the occurrence of lagging chromosomes but no chromosome bridges indicative of mitotic checkpoint impairment. Intriguingly, in the long-term (four 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.

Abstract

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 also in vivo. 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 post 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, while the aneuploidy phenotype involved the occurrence of lagging chromosomes but no chromosome bridges indicative of mitotic checkpoint impairment. Intriguingly, in the long-term (four 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2013
Deposited On:31 Dec 2013 10:58
Last Modified:05 Apr 2016 17:19
Publisher:American Association for Cancer Research
ISSN:0008-5472
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1158/0008-5472.CAN-13-2040
PubMed ID:24362914

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