Combined mutation of
            <i>Vhl</i>
            and
            <i>Trp53</i>
            causes renal cysts and tumours in mice

Albers, Joachim; Rajski, Michal; Schönenberger, Désirée; Harlander, Sabine; Schraml, Peter; Teichman, Adriana von; Georgiev, Strahil; Wild, Peter J.; Moch, Holger; Krek, Wilhelm; Frew, Ian J.

doi:10.1002/emmm.201202231

Cited by 82 publications

(96 citation statements)

References 50 publications

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“…Immunohistochemistry and immunofluorescence of formalinfixed paraffin-embedded tissues were performed as previously described (6,8) using antibodies listed in Supplementary Materials and Methods.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Primary adult mouse renal epithelial cells were cultured for 3 days and infected with Adeno-GFP (Vector Biolabs, 1060) or Adeno-Cre (Vector Biolabs, 1700) as described (8). mRNA was isolated 4 days after adenovirus infection, and Cy3-and Cy5-labeled cDNA from GFP and Cre samples was competitively hybridized to Mouse GE 4 Â 44 K v2 Microarrays (Agilent).…”

Section: Microarraysmentioning

confidence: 99%

“…There are currently no autochthonous mouse models that fully reproduce all of the characteristic morphologic and invasive properties of human ccRCC; however, consistent with the hypothesis that multiple cooperating mutations are required for ccRCC development, kidney epithelial cell-specific codeletion of Vhl with Pten (6), or with Kif3a to genetically ablate primary cilia (7), caused the formation of simple and atypical cystic lesions that are similar to the ccRCC precursor cystic lesions found in the kidneys of patients with inherited VHL disease. Deletion of Vhl together with homozygous loss of Trp53 (8) or with heterozygous loss of Bap1 (9) gave rise to very similar phenotypes, including simple and atypical cystic lesions as well as tumors containing cells that display cytoplasmic clearing and elevated mTORC1 activity, recapitulating many of the cellular and molecular changes that are characteristic of human ccRCC.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Immunohistochemistrymentioning

confidence: 99%

Section: Microarraysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…Immunohistochemistry and immunofluorescence of formalin-fixed paraffin-embedded kidneys was performed as described 43 with the following antibodies: a-ATPV1B1 (gift from C. Wagner), a-Aqp2 (gift from J. Loffing), BrdU (MAP3510; EMD Millipore), cleaved caspase 3 (9661; Cell Signaling Technology), a-Glut1 (Ab14683; Abcam, Inc.), a-HIF1a (NB100-105; Novus Biologicals ), a-Ki67 (TEC-3; DakoCytomation), a-NaPi (gift from J. Biber), a-NCC (AB3553; EMD Millipore), a-THP (sc-20631; Santa Cruz Biotechnology) and a-acetylated tubulin (T6793; Sigma-Aldrich). Secondary Alexa 488-or Alexa 568-coupled antibodies were from Life Technologies.…”

Section: Immunohistochemistrymentioning

confidence: 99%

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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“…Mouse embryonic stem cells were a gift of Kurt Bürki (Institute of Physiology, University of Zurich) and cultured in N2B27+ 2i medium. Murine primary kidney epithelial cells were isolated and cultured as described before (53). Endometrial epithelial cells were isolated and cultured as described (54).…”

Section: Methodsmentioning

confidence: 99%