Tumor Suppressor VHL Functions in the Control of Mitotic Fidelity

Hell, Michael P.; Duda, Maria; Weber, Thomas; Moch, Holger; Krek, Wilhelm

doi:10.1158/0008-5472.can-13-2040

Cited by 27 publications

(23 citation statements)

References 31 publications

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“…32 Ischemic damage to induce cellular proliferation in Vhl null kidney tubules increased the frequency of misoriented epithelial cell divisions, correlating with the formation of microcysts in these animals. 33 Consistent with the idea that Vhl/Kif3a mutation compromises two different mechanisms that ensure oriented cell division, anaphases in cystic epithelia of Kif3a Vhl deletion in mouse proximal tubular epithelial cells caused cyst formation in a small fraction of older mice. 34 Because this phenotype could be rescued by codeletion of Arnt, encoding HIF1b (the dimerization partner of HIF1a and HIF2a that is necessary for transcriptional activation), but not by codeletion of Hif1a, 34 it is possible that the combined activities of HIF1a and HIF2a may promote cyst formation in Kif3a D/D ;Vhl D/D mice.…”

Section: Discussionsupporting

confidence: 79%

Combined Deletion of Vhl and Kif3a Accelerates Renal Cyst Formation

Lehmann

Vicari

Wild

et al. 2015

Journal of the American Society of Nephrology

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A subset of familial and sporadic clear cell renal cell carcinomas (ccRCCs) is believed to develop from cystic precursor lesions. Loss of function of the von Hippel-Lindau tumor suppressor gene (VHL) predisposes renal epithelial cells to loss of the primary cilium in response to specific signals. Because the primary cilium suppresses renal cyst formation, loss of the cilium may be an initiating event in the formation of ccRCC. To test this hypothesis, we analyzed the consequences of inducible renal epithelium-specific deletion of Vhl together with ablation of the primary cilium via deletion of the kinesin family member 3A (Kif3a) gene. We developed a microcomputed tomography-based imaging approach to allow quantitative longitudinal monitoring of cystic burden, revealing that combined loss of Vhl and Kif3a shortened the latency of cyst initiation, increased the number of cysts per kidney, and increased the total cystic burden. In contrast with findings in other cystic models, cysts in Kif3a mutant mice did not display accumulation of hypoxia-inducible factor 1-a (HIF1a), and deletion of both Hif1a and Kif3a did not affect cyst development or progression. Vhl/Kif3a double mutation also increased the frequency of cysts that displayed multilayered epithelial growth, which correlated with an increased frequency of misoriented cystic epithelial cell divisions. These results argue against the involvement of HIF1a in promoting renal cyst growth and suggest that the formation of simple and atypical renal cysts that resemble ccRCC precursor lesions is greatly accelerated by the combined loss of Vhl and the primary cilium.

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Section: Discussionsupporting

confidence: 79%

Combined Deletion of Vhl and Kif3a Accelerates Renal Cyst Formation

Lehmann

Vicari

Wild

et al. 2015

Journal of the American Society of Nephrology

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“…We have recently shown that in an ischemic injury/regeneration model, kidney epithelial cells of Vhl D/D mice display high rates of aneuploidy (14). Hence, we used this in vivo model to explore miR-28-5p function with respect to its requirement for the development of chromosomal instability upon Vhl ablation.…”

Section: Delivery Of Lna-based Mir-28-5p Inhibitors Rescue Vhl-loss-imentioning

confidence: 99%

miR-28-5p Promotes Chromosomal Instability in VHL-Associated Cancers by Inhibiting Mad2 Translation

et al. 2014

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Chromosomal instability enables tumor development, enabled in part by aberrant expression of the mitotic checkpoint protein Mad2. Here we identify a novel regulatory mechanism for Mad2 expression involving miR-28-5p-mediated inhibition of Mad2 translation, and we demonstrate that this mechanism is triggered by inactivation of the tumor suppressor VHL, the most common event in clear cell renal cell carcinoma (ccRCC). In VHL-positive cancer cells, enhanced expression of miR-28-5p diminished Mad2 levels and promoted checkpoint weakness and chromosomal instability. Conversely, in checkpoint-deficient VHL-negative renal carcinoma cells, inhibition of miR-28-5p function restored Mad2 levels, mitotic checkpoint proficiency, and chromosomal stability. Notably, chromosome missegregation errors and aneuploidy that were produced in a mouse model of acute renal injury (as a result of kidney-specific ablation of pVHL function) were reverted in vivo also by genetic inhibition of miR-28-5p. Finally, bioinformatic analyses in human ccRCC associated loss of VHL with increased miR-28-5p expression and chromosomal instability. Together, our results defined miR-28-5p as a critical regulator of Mad2 translation and mitotic checkpoint function. By identifying a potential mediator of chromosomal instability in VHL-associated cancers, our work also suggests a novel microRNA-based therapeutic strategy to target aneuploid cells in VHL-associated cancers. Cancer Res; 74(9); 2432-43. Ó2014 AACR.

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“…10), regulation of NF-kB activity (11), maintenance of the primary cilium (12), activation of p53 (13), secretion of extracellular matrix components (14), promotion of DNA double-strand repair (15), regulation of the plane of cellular division (16,17), and suppression of aneuploidy (16,18). The combined loss of several or all of pVHL's functions could contribute to tumor initiation and progression.…”

Section: Introductionmentioning

confidence: 99%

Formation of Renal Cysts and Tumors in Vhl/Trp53-Deficient Mice Requires HIF1α and HIF2α

et al. 2016

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The von Hippel-Lindau (VHL) tumor suppressor gene is inactivated in the majority of clear cell renal cell carcinomas (ccRCC), but genetic ablation of Vhl alone in mouse models is insufficient to recapitulate human tumorigenesis. One function of pVHL is to regulate the stability of the hypoxia-inducible factors (HIF), which become constitutively activated in the absence of pVHL. In established ccRCC, HIF1a has been implicated as a renal tumor suppressor, whereas HIF2a is considered an oncoprotein. In this study, we investigated the contributions of HIF1a and HIF2a to ccRCC initiation in the context of Vhl deficiency. We found that deleting Vhl plus Hif1a or Hif2a specifically in the renal epithelium did not induce tumor formation. However, HIF1a and HIF2a differentially regulated cell proliferation, mitochondrial abundance and oxidative capacity, glycogen accumulation, and acquisition of a clear cell phenotype in Vhldeficient renal epithelial cells. HIF1a, but not HIF2a, induced Warburg-like metabolism characterized by increased glycolysis, decreased oxygen consumption, and decreased ATP production in mouse embryonic fibroblasts, providing insights into the cellular changes potentially occurring in Vhl mutant renal cells before ccRCC formation. Importantly, deletion of either Hif1a or Hif2a completely prevented the formation of renal cysts and tumors in Vhl/Trp53 mutant mice. These findings argue that both HIF1a and HIF2a exert protumorigenic functions during the earliest stages of cyst and tumor formation in the kidney. Cancer Res; 76(7); 2025-36. Ó2016 AACR.

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Tumor Suppressor VHL Functions in the Control of Mitotic Fidelity

Cited by 27 publications

References 31 publications

Combined Deletion of Vhl and Kif3a Accelerates Renal Cyst Formation

Combined Deletion of Vhl and Kif3a Accelerates Renal Cyst Formation

miR-28-5p Promotes Chromosomal Instability in VHL-Associated Cancers by Inhibiting Mad2 Translation

Formation of Renal Cysts and Tumors in Vhl/Trp53-Deficient Mice Requires HIF1α and HIF2α

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