The VHL tumor suppressor in development and disease: Functional studies in mice by conditional gene targeting

Haase, Volker H.

doi:10.1016/j.semcdb.2005.03.006

Cited by 73 publications

(59 citation statements)

References 113 publications

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“…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.

129

107

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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.

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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.

129

107

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“…For example, whereas HIF target genes involved in glycolysis, such as PGK, are regulated by the HIF-1 isoform, the hypoxic induction of VEGF and liver angiogenesis appear to be predominantly dependent on the HIF-2 isoform. [58][59][60][61] Thus, targeting HIF could be an important pathway by which to regulate VEGF and angiogenesis in liver.…”

Section: Emerging Therapies For Vascular Diseases Of the Livermentioning

confidence: 99%

Vascular biology and pathobiology of the liver: Report of a single-topic symposium

2008

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Portal hypertension and its complications account for the majority of morbidity and mortality that occurs in patients with cirrhosis. In addition to portal hypertension, a number of other vascular syndromes are also of great importance, especially the ischemia-reperfusion (IR) injury. With the identification of major vascular defects that could account for many of the clinical sequelae of these syndromes, the liver vasculature field has now integrated very closely with the broader vascular biology discipline. In that spirit, the Vascular Cell Signaling Mediated by NO. Endothelial cells (ECs) produce NO through the enzyme endothelial NO synthase (eNOS). NO then regulates important vascular functions, such as vascular tone, angiogenesis, and arterial remodeling. 1 eNOS is regulated in a multiprotein complex (Fig. 1), which includes the activating kinase, Akt1 and putative negative regulator caveolin-1 (Cav-1). Although eNOS Ϫ/Ϫ mice evidence impaired angiogenesis, overexpression of a constitutively active allele of eNOS that mimics the phosphorylated and active state rescues these angiogenic defects. 2 Because eNOS is an EC-specific Akt substrate, ECs from mice lacking the Akt1 isoform also have defects in eNOS phosphorylation, NO production, and angiogenesis which are correspondingly rescued by Akt1 overexpression. 3 One key mechanism by which the Akt-eNOS axis promotes angiogenesis in vivo is through mobilization of endothelial progenitor cells and EC migration to sites of vascular injury. In contradistinction to AKT, Cav-1 is a negative regulator of eNOS. Mice deficient in Cav-1 have defective mechanotransduction, calcium signaling, prostacyclin production, and elevated NO production indicating that endothelial Cav-1 also importantly regulates vascular function by regulating eNOS and other signaling pathways. 4 Upon its generation in ECs, NO also acts on adjacent vascular effector cells to modulate vascular tone, cellular proliferation, apoptosis, migration, and synthesis of extracellular matrix (Fig. 2). NO acts in part by stimulating soluble guanylate cyclase (sGC) to produce intracellular Abbreviations: Cav-

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“…ese data are consistent with observations in psoriatic skin biopsies (highly vascularised tissues) because the absence of the VHL expression and the presence of HDAC1 [21] could explain the high production of VEGF. Additionally, mice with a vhl-/-epidermal deletion show an increase in erythropoietin and in skin vascularisation; [13] vhl-/-keratinocytes over-express HIF1alpha and HIF-2alpha, [4] which causes the increase of the expression of HIF target genes such as VEGF, PGK, GLUT1, INOS mRNAs and erythropoietin. [29] Studying the opposite biological phenomenon in keratinocytes, the upregulation of VHL decreased the basal levels of HIF-1alpha in the cytoplasm and decreased VEGF production (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…e angiogenic process can be triggered by several molecules produced by epithelial cells, -broblasts, endothelial cells and tumoral cells, and vascular endothelial growth factor (VEGF) is the principal proangiogenic factor released by these cells. [1] In hypoxic tumoral cells, hypoxia induced factor 1 (HIF-1) is the main transcription factor involved in the expression of VEGF; [2] histone deacetylase 1 (HDAC1) [3] and the tumour suppressor protein von Hippel-Lindau (VHL) [4] regulate the levels of the HIF-1alpha subunit in the cellular cytoplasm. In keratinocytes, factors such as transforming growth factor-alpha (TGF-alpha), epidermal growth factor, and insulin-like growth factor I and II(IGF-I/II) are involved in the induction of VEGF production.…”

mentioning

confidence: 99%

Vascular endothelial growth factor production is induced by histone deacetylase 1 and suppressed by von Hippel-Lindau protein in HaCaT cells

Reynoso-Roldán

Roldán

Cancino‐Díaz³

et al. 2012

CIM

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Purpose: In hypoxic tumoral tissues, vascular endothelial growth factor (VEGF) expression is positively regulated by histone deacetylase 1 (HDAC1) and negatively regulated by the tumour suppressor protein von Hippel-Lindau (VHL) via hypoxia induced factor-1 alpha (HIF-1alpha). It has been reported that VEGF, HDAC1 and LL-37, but not VHL, are over-expressed in psoriatic skin. Although HIF-1alpha is constitutively expressed in normal keratinocytes, it is not known if HDAC1 and VHL can regulate VEGF production in these cells.Methods: e participation of HDAC1 and VHL in the regulation of VEGF expression in HDAC1-, VHL-and LL-37-transfected HaCaT cells, and in HaCaT cells treated with HDAC1 inhibitors, was studied.Results: e production of VEGF was increased in HDAC1-and LL-37-transfected HaCaT cells and maintained in VHL-transfected cells under hypoxic conditions; meanwhile, VEGF production decreased in HaCaT cells treated with TSA, in cells transfected with HDAC1-siRNA, in cells co-transfected with HIF-1alpha-siRNA and pHDAC-1 and in VHL-transfected HaCaT cells. e levels of cytoplasmic HIF-1alpha were high in pLL37-transfected cells and low in pVHL-and pHDAC1-transfected cells; however, HIF-1alpha was detected in the nucleus of the HDAC1-transfected cells. e expression of VEGF was high in cells co-transfected with pHDAC1-and pLL-37, and the expression decreased when pVHL was present.Conclusions: ese data demonstrate that HDAC1, LL-37 and VHL can modulate the production of VEGF via HIF-1alpha in HaCaT cells.

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The VHL tumor suppressor in development and disease: Functional studies in mice by conditional gene targeting

Cited by 73 publications

References 113 publications

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

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

Vascular biology and pathobiology of the liver: Report of a single-topic symposium

Vascular endothelial growth factor production is induced by histone deacetylase 1 and suppressed by von Hippel-Lindau protein in HaCaT cells

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