pVHL and PTEN tumour suppressor proteins cooperatively suppress kidney cyst formation

Frew, Ian J.; Thoma, Claudio R.; Georgiev, Strahil; Minola, Andrea; Hitz, Manuela; Montani, M.; Moch, Holger; Krek, Wilhelm

doi:10.1038/emboj.2008.96

Cited by 141 publications

(165 citation statements)

References 32 publications

Supporting

Mentioning

150

Contrasting

Unclassified

Order By: Relevance

“…Previous studies demonstrated that inactivation of Vhl in proximal tubules can result in renal cyst development in aged mice 35 or after combined deletion of the tumor suppressor PTEN. 36 TAL-restricted Vhl inactivation in our study did not lead to renal cysts or renal cell carcinomas in mice up to an age of 18 months.…”

Section: Vhl Inactivation In the Tal Does Not Alter Renal Morphologysupporting

confidence: 41%

Hypoxia-Inducible Transcription Factors Stabilization in the Thick Ascending Limb Protects against Ischemic Acute Kidney Injury

Schley

Klanke²,

Schödel³

et al. 2011

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Hypoxia-inducible transcription factors (HIF) protect cells against oxygen deprivation, and HIF stabilization before ischemia mitigates tissue injury. Because ischemic acute kidney injury (AKI) often involves the thick ascending limb (TAL), modulation of HIF in this segment may be protective. Here, we generated mice with targeted TAL deletion of the von Hippel-Lindau protein (Vhl), which mediates HIF degradation under normoxia, using Tamm-Horsfall protein (Thp)-driven Cre expression. These mice showed strong expression of HIF-1␣ in TALs but no changes in kidney morphology or function under control conditions. Deficiency of Vhl in the TAL markedly attenuated proximal tubular injury and preserved TAL function following ischemia-reperfusion, which may be partially a result of enhanced expression of glycolytic enzymes and lactate metabolism. These results highlight the importance of the thick ascending limb in the pathogenesis of AKI and suggest that pharmacologically targeting the HIF system may have potential to prevent and mitigate AKI.

show abstract

Section: Vhl Inactivation In the Tal Does Not Alter Renal Morphologysupporting

confidence: 41%

Hypoxia-Inducible Transcription Factors Stabilization in the Thick Ascending Limb Protects against Ischemic Acute Kidney Injury

Schley

Klanke²,

Schödel³

et al. 2011

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…This observation has remained an enigma since this report by Gnarra et al (27) was published in 1997. Vhl −/− mice die during gestation (27), but simultaneous inactivation of both Vhl alleles in kidney epithelial cells similarly failed to induce renal tumorigenesis (28)(29)(30)(31). These experiments are confounded by lack of knowledge about the cell type of origin of ccRCC and restricted Cre expression (28-31); however, as we show, even when Vhl is inactivated in multipotent NPCs, Vhl loss is insufficient for renal tumorigenesis.…”

Section: Discussionmentioning

confidence: 85%

Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis

Wang

Wolff

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

131

107

View full text Add to dashboard Cite

Significance Despite the discovery of the von Hippel–Lindau ( VHL ) gene in 1993, and that inactivating germ-line mutations of VHL cause multiple kidney lesions, including clear-cell renal cell carcinoma (ccRCC), Vhl inactivation in the mouse does not lead to ccRCC and a mouse model has been lacking. We discovered that the BRCA1-associated protein-1 ( BAP1 ) two-hit tumor suppressor gene is mutated in ccRCC, and one BAP1 allele is frequently somatically codeleted with VHL in tumors. In the mouse, Vhl and Bap1 are on different chromosomes. We show that SIX homeobox 2 ( Six2 ) -Cre;Vhl F/F ;Bap1 F/ + mice develop premalignant lesions and malignant ccRCC resembling VHL syndrome. More broadly, differences in tumor predisposition across species may result from differences in the location of two-hit tumor suppressor genes across the genome.

show abstract

“…Deletion of Vhlh in pancreatic islets of Rip2-Cre; Vhlh fl/fl mice (hereafter referred to as Vhlh −/− ) was confirmed by PCR-mediated detection of the recombined Vhlh allele, as identical sized bands were generated by these PCR reactions as from kidney DNA derived from a kidneyspecific Vhlh −/− mouse model ( Fig. 1C; Frew et al 2008). Immunohistochemical analysis of islets of 26-wk-old Vhlh −/− mice revealed strong nuclear accumulation of HIF1␣ (Fig.…”

Section: Deletion Of Vhlh Leads To the Accumulation Of Transcriptionamentioning

confidence: 91%

“…As insulin secretion from ␤ cells is dependent on a rise in cellular ATP levels generated by glucose-stimulated ) was compared with kidney DNA of a kidney-specific Vhlh −/− mouse model (positive control: C Vhlh −/− ; negative control: C Vhlh fl/wt ) (Frew et al 2008). (D) IHC using pancreatic sections of control mice and conditional Vhlh −/− mice (bar, 100 µm; n = 3 mice).…”

Section: Vhlh-deficient Mice Display Impaired Glucose Tolerancementioning

confidence: 99%

pVHL is a regulator of glucose metabolism and insulin secretion in pancreatic β cells

Zehetner¹,

Danzer²,

Collins³

et al. 2008

Genes Dev.

Self Cite

108

View full text Add to dashboard Cite

Insulin secretion from pancreatic ␤ cells is stimulated by glucose metabolism. However, the relative importance of metabolizing glucose via mitochondrial oxidative phosphorylation versus glycolysis for insulin secretion remains unclear. von Hippel-Lindau (VHL) tumor suppressor protein, pVHL, negatively regulates hypoxia-inducible factor HIF1␣, a transcription factor implicated in promoting a glycolytic form of metabolism. Here we report a central role for the pVHL-HIF1␣ pathway in the control of ␤-cell glucose utilization, insulin secretion, and glucose homeostasis. Conditional inactivation of Vhlh in ␤ cells promoted a diversion of glucose away from mitochondria into lactate production, causing cells to produce high levels of glycolytically derived ATP and to secrete elevated levels of insulin at low glucose concentrations. Vhlh-deficient mice exhibited diminished glucose-stimulated changes in cytoplasmic Ca 2+ concentration, electrical activity, and insulin secretion, which culminate in impaired systemic glucose tolerance. Importantly, combined deletion of Vhlh and Hif1␣ rescued these phenotypes, implying that they are the result of HIF1␣ activation. Together, these results identify pVHL and HIF1␣ as key regulators of insulin secretion from pancreatic ␤ cells. They further suggest that changes in the metabolic strategy of glucose metabolism in ␤ cells have profound effects on whole-body glucose homeostasis.[Keywords: HIF; VHL; glucose intolerance; islet; pancreas] Supplemental material is available at http://www.genesdev.org. Received July 14, 2008; revised version accepted September 5, 2008. During adulthood, cell type-specific growth that exceeds the normal physiological constraints is a common feature of adaptive processes of tissues to changes in metabolic homeostasis and underlies the development of many human diseases, including cancer, heart disease, and diabetes (De Boer et al. 2003;Bouwens and Rooman 2005). Adaptive cell mass expansion, whether neoplastic or nonneoplastic, creates a requirement for compensatory neovascularization to supply oxygen, metabolic substances, and growth/survival factors to the growing tissue (Marti 2005). Therefore, adaptive cell growth responses are generally accompanied, at least initially, by relative states of hypoxia as a result of a mismatch between oxygen demand caused by tissue expansion and oxygen supply provided by the vasculature. An immediate consequence of decreased tissue oxygen availability is that cells shift cellular fuel metabolism from mitochondrial respiration to glycolysis and activate an angiogenic program to increase oxygen delivery in order to overcome the imbalance between tissue mass and vascularization (Semenza 2001;Brahimi-Horn et al. 2007). In this way, tissue function is supported and further mass expansion can occur.At the molecular level, the central regulators of the cellular response to low-oxygen availability are the hypoxia-inducible transcription factors (HIF). HIF are heterodimeric transcription factors composed of HIF1␣, HIF2␣, or HI...

show abstract

pVHL and PTEN tumour suppressor proteins cooperatively suppress kidney cyst formation

Cited by 141 publications

References 32 publications

Hypoxia-Inducible Transcription Factors Stabilization in the Thick Ascending Limb Protects against Ischemic Acute Kidney Injury

Hypoxia-Inducible Transcription Factors Stabilization in the Thick Ascending Limb Protects against Ischemic Acute Kidney Injury

Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis

pVHL is a regulator of glucose metabolism and insulin secretion in pancreatic β cells

Contact Info

Product

Resources

About