Binding of the von Hippel-Lindau Tumor Suppressor Protein to Elongin B and C

Kibel, Adam S.; Iliopoulos, Othon; DeCaprio, James A.; Kaelin, William G.

doi:10.1126/science.7660130

Cited by 626 publications

(474 citation statements)

References 19 publications

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“…The importance of gene expression being regulated at the level of transcriptional elongation was recently highlighted in studies demonstrating that the product of the von HippelLindau (VHL) tumour suppressor gene negatively regulates the elongation factor elongin (SIII). These studies found that mutations in the VHL protein interfered with this regulatory mechanism and led to a failure to regulate transcription at the level of elongation which thereby predisposed cells of the eye, kidney and central nervous system to carcinogenesis (Duan et al, 1995;Kibel et al, 1995;Aso et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Microsatellite deletions in the c-myb transcriptional attenuator region associated with over-expression in colon tumour cell lines

et al. 1997

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In the hemopoietic system c-myb expression is required for proliferation of immature cells and its downregulation is required for di erentiation. In colonic mucosa c-myb expression occurs at levels comparable to immature hemopoietic cells. Inhibition of c-myb expression in colon cell lines, using anti-sense oligonucleotides, indicates that c-myb expression is required for proliferation. However, the mechanism of c-myb regulation during colon cell di erentiation has not been explored. Using the LIM1215 and CaCo-2 colon carcinoma cell lines induced to di erentiate with sodium butyrate, we demonstrate that c-myb mRNA is downregulated as an early event in di erentiation by a mechanism involving transcriptional attenuation in intron 1. By analogy with procaryotic and eucaryotic genes, transcriptional attenuation probably occurs in a region containing nineteen consecutive thymidine residues. Computer prediction of the secondary structure of the nascent mRNA chain encoded by this region suggests a strong potential for stem-loop formation. Sequence analysis of several colon tumour cell lines reveals mutations in this region that may disrupt transcriptional attenuation and result in the increased c-myb expression observed in colon tumours and tumour cell lines.

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Section: Discussionmentioning

confidence: 99%

Microsatellite deletions in the c-myb transcriptional attenuator region associated with over-expression in colon tumour cell lines

et al. 1997

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“…d-VHL has an overall 22% identity to h-VHL and is 50% similar when conserved amino acid changes were considered ( Figure 1b). In the two functionally signi®cant protein interaction domains, human residues 113 ± 121 and 157 ± 172 that encompass the protein kinase Cl (PKCl) and the elongin C binding sites, respectively (Okuda et al, 1999;Kibel et al, 1995), the conservation is signi®cantly higher at 67 and 76%.…”

Section: Cloning Of the D-vhl Gene Sequencementioning

confidence: 99%

Tracheal development and the von Hippel–Lindau tumor suppressor homolog in Drosophila

et al. 2000

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“…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.…”

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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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Binding of the von Hippel-Lindau Tumor Suppressor Protein to Elongin B and C

Cited by 626 publications

References 19 publications

Microsatellite deletions in the c-myb transcriptional attenuator region associated with over-expression in colon tumour cell lines

Microsatellite deletions in the c-myb transcriptional attenuator region associated with over-expression in colon tumour cell lines

Tracheal development and the von Hippel–Lindau tumor suppressor homolog in Drosophila

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

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