Up-Regulation of Vascular Endothelial Growth Factor in Stromal Cells of Hemangioblastomas Is Correlated with Up-Regulation of the Transcription Factor HRF/HIF-2α

Flamme, Ingo; Krieg, Marion; Plate, Karl H.

doi:10.1016/s0002-9440(10)65541-1

Cited by 105 publications

(61 citation statements)

References 26 publications

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“…A question arises with respect to FGF-2 function: Does FGF-2 release result in the induction of VEGF expression in the angiogenic loci, and if so, by what cell types? Several studies have indicated that VEGF is highly expressed in the hypoxic regions of the tumor as would be expected, but is also expressed in tissue stroma (Brown et al, 1993;Flamme et al, 1998;Fukumura et al, 1998;Huang et al, 1998;Levine et al, 1998;Senger et al, 1994). The specific mechanism controlling stromal cell VEGF expression is unclear.…”

mentioning

confidence: 87%

Fibroblast Growth Factor 2 Activation of Stromal Cell Vascular Endothelial Growth Factor Expression and Angiogenesis

Claffey

Abrams²,

Shih

et al. 2001

Laboratory Investigation

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mentioning

confidence: 87%

Fibroblast Growth Factor 2 Activation of Stromal Cell Vascular Endothelial Growth Factor Expression and Angiogenesis

Claffey

Abrams²,

Shih

et al. 2001

Laboratory Investigation

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“…120 Whether this requires tissue-specific transcriptional co-activators or repressors, certain DNA or protein modifications or other signaling events warrants further investigation. 131 Whatever the underlying mechanisms, clinical studies have also demonstrated a correlation between HIF-2a expression and the development of VHL-associated angiogenic lesions, 132 suggesting that pharmacological targeting of HIF-2 may by an effective therapy for the treatment of these tumors. pVHL-and pVHL/ARNT-deficient liver tissues are histologically similar and direct comparison of gene expression changes has not revealed major differences 31 (also VH Haase et al, unpublished observation), suggesting that the effects of pVHL gene deletion in the liver are largely HIF mediated.…”

Section: Vhl Phenotypes In Non-renal Tissues: Is It All Hif?mentioning

confidence: 99%

The VHL tumor suppressor and HIF: insights from genetic studies in mice

2008

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The von Hippel-Lindau tumor suppressor gene product, pVHL, functions as the substrate recognition component of an E3-ubiquitin ligase, which targets the oxygen-sensitive a-subunit of hypoxia-inducible factor (HIF) for rapid proteasomal degradation under normoxic conditions and as such plays a central role in molecular oxygen sensing. Mutations in pVHL can be found in familial and sporadic clear cell carcinomas of the kidney, hemangioblastomas of the retina and central nervous system, and pheochromocytomas, underscoring its gatekeeper function in the pathogenesis of these tumors. Tissue-specific gene targeting of VHL in mice has demonstrated that efficient execution of pVHL-mediated HIF proteolysis under normoxia is fundamentally important for survival, proliferation, differentiation and normal physiology of many cell types, and has provided novel insights into the biological function of individual HIF transcription factors. In this review, we discuss the role of HIF in the development of the VHL phenotype. Germ-line mutations in the von Hippel-Lindau tumor (VHL) suppressor can be found in patients with VHL disease, a rare familial tumor syndrome characterized by the development of highly vascularized tumors in multiple organs. Major clinical manifestations of VHL disease include hemangioblastomas of the retina and central nervous system (CNS), renal cysts and renal cell carcinoma of the clear cell type (CC-RCC), pancreatic cysts and tumors, as well as pheochromocytomas. 1 The VHL tumor suppressor is also mutated in the majority of sporadic CC-RCCs, 2 highlighting its critical and central role in the regulation of cell growth and differentiation of epithelial kidney cells. Although the molecular function of the VHL gene product, pVHL, was initially not known when it was first identified by positional cloning in 1993, 3 observations that oxygen-dependent regulation of hypoxia-inducible genes was lost in VHL-deficient cell lines suggested a role for pVHL in oxygen sensing. [4][5][6] In a seminal paper, Maxwell et al. 7 showed that pVHL was critical for targeting the a-subunit of hypoxia-inducible factor (HIF) for oxygen-dependent proteolysis, thus providing a direct molecular link between VHLassociated tumorigenesis and oxygen sensing via HIF. HIFs belong to the PAS (Per-arylhydrocarbon receptor nuclear translocator (ARNT)-Sim) family of basic helix-loop-helix (bHLH) transcription factors and bind DNA as heterodimers. They consist of an oxygen-sensitive a-subunit and a constitutively expressed b-subunit, also known as ARNT or HIF-b. pVHL associates with the elongins B and C, cullin2 and Rbx [8][9][10][11][12] and functions as the substrate recognition component of an E3-ubiquitin ligase that ubiquitylates HIF-a. [13][14][15][16][17][18][19] All three HIF a-subunits, HIF-1a, HIF-2a and HIF-3a interact with pVHL. 7,20 This pVHL-HIF-a interaction is highly conserved between species, requires iron-and oxygen-dependent hydroxylation of specific proline residues (Pro402 and Pro564 in human HIF-1a; Pro405 and Pro531 in ...

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“…These lesions are typically cystic tumors of endothelial cells and lipid-filled stromal cells embedded in capillaries [Kanno et al, 1994;Richard et al, 1998]. Stromal cells may play a neoplastic role by releasing angiogenic factors, like vascular endothelial growth factors (VEGF), whereas vascular cells appear to be nonneoplastic [Chan et al, 1999;Flamme et al, 1998;Lee et al, 1998;Morii et al, 1993;Vortmeyer et al, 1997;Wizigmann-Voos et al, 1995]. CNS hemangioblastomas are typically located in the cerebellum, but can also occur at the brainstem, spinal cord, and rarely, at the lumbosacral nerve roots and supratentorial [Neumann et al, 1995].…”

Section: Introductionmentioning

confidence: 99%

Genetic analysis of von Hippel-Lindau disease

et al. 2010

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Mutations in the von Hippel-Lindau (VHL) gene are responsible for VHL disease, congenital polycythemia, and are found in many sporadic tumor types as well. Reports of VHL mutations are dispersed throughout original articles and databases that have not been recently updated. We compiled a comprehensive mutation table of 1,548 germline and somatic VHL mutations, derived from this protein of only 213 amino acids. We describe detailed phenotype and gene mutation information for 945 VHL families, including 30 previously unpublished kindreds from The Netherlands (six novel mutations). These data represent the most extensive catalog of germline VHL mutations to date. We also review VHL disease, known and theorized pathogenesis of common VHL manifestations, and genotype-phenotype correlations. Analysis of all VHL families, excluding germline mutations resulting in congenital polycythemias, describes the spectrum of mutation types: 52% missense, 13% frameshift, 11% nonsense, 6% in-frame deletions/insertions, 11% large/complete deletions, and 7% splice mutations. This easy-to-use compilation of VHL mutations is intended to facilitate research and function as a necessary adjunct for physicians when providing patient information. Hum Mutat 31:521-537,

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Up-Regulation of Vascular Endothelial Growth Factor in Stromal Cells of Hemangioblastomas Is Correlated with Up-Regulation of the Transcription Factor HRF/HIF-2α

Cited by 105 publications

References 26 publications

Fibroblast Growth Factor 2 Activation of Stromal Cell Vascular Endothelial Growth Factor Expression and Angiogenesis

Fibroblast Growth Factor 2 Activation of Stromal Cell Vascular Endothelial Growth Factor Expression and Angiogenesis

The VHL tumor suppressor and HIF: insights from genetic studies in mice

Genetic analysis of von Hippel-Lindau disease

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