von Hippel–Lindau protein binds hyperphosphorylated large subunit of RNA polymerase II through a proline hydroxylation motif and targets it for ubiquitination

Кузнецова, А. В.; Meller, Jarosław; Schnell, Per-Olof; Nash, James A.; Ignacak, Monika; Sánchez, Yolanda; Conaway, Joan Weliky; Conaway, Ronald C.; Czyzyk-Krzeska, Maria F.

doi:10.1073/pnas.0436037100

Cited by 213 publications

(172 citation statements)

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“…51 Furthermore, pVHL has been shown to regulate microtubule stability and cilia maintenance [52][53][54][55] and controls the activity of plant homeodomain protein Jade-1, 56,57 and atypical protein kinase C isoforms. [58][59][60][61][62] Other pVHL targets include a KRAB-A domain protein, VHLak, repressing HIF transcriptional activity, 63 de-ubiquitinating enzymes, 64 the large subunit of RNA polymerase II 65 and the RNA-binding protein hnRNP A2. 66 How these HIF-independent pVHL functions and recently discovered protein interactions exactly contribute to the initiation and progression of VHL-associated tumorigenesis is unclear and requires further investigation.…”

Section: Biological Functions Not Involving Hifmentioning

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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Section: Biological Functions Not Involving Hifmentioning

confidence: 99%

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

2008

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“…These studies predict that other proteins directly binding pVHL might contain sites of prolyl hydroxylation. Interestingly, the transcriptionally active hyperphosphorylated large subunit of RNA polymerase II (Rbp1) has been identified as a second hydroxylationdependent binding partner of pVHL (18). However, it seems unlikely that this interaction is responsible for the observed effects on matrix assembly, suggesting that there might be other hydroxylated species that account for this function.…”

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confidence: 99%

Interaction of Hydroxylated Collagen IV with the von Hippel-Lindau Tumor Suppressor

Grosfeld

Stolze

Cockman

et al. 2007

Journal of Biological Chemistry

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The von Hippel-Lindau tumor suppressor (pVHL) targets hydroxylated ␣-subunits of hypoxia-inducible factor (HIF) for ubiquitin-mediated proteasomal destruction through direct interaction with the hydroxyproline binding pocket in its ␤-domain. Although disruption of this process may contribute to VHL-associated tumor predisposition by up-regulation of HIF target genes, genetic and biochemical analyses support the existence of additional functions, including a role in the assembly of extracellular matrix. In an attempt to delineate these pathways, we searched for novel pVHL-binding proteins. Here we report a direct, hydroxylation-dependent interaction with ␣-chains of collagen IV. Interaction with pVHL was also observed with fibrillar collagen chains, but not the folded collagen triple helix. The interaction was suppressed by a wide range of tumor-associated mutations, including those that do not disturb the regulation of HIF, supporting a role in HIF-independent tumor suppressor functions.

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Section: Introductionmentioning

confidence: 99%

“…It is established that the encoded protein, VHL (von Hippel-Lindau), is required for regulation of hypoxia-inducible factor (HIF) explaining why loss-of-function of VHL is associated with angiogenic signaling and other aspects of the cancer phenotype (Wang and Semenza, 1993;Maxwell et al, 1999). VHL also has effects that are independent of its role in degradation of HIF-␣ subunits, including regulation of RNA polymerase II, atypical protein kinase C, cellular senescence, matrix assembly, and microtubule stabilization (Ohh et al, 1998;Okuda et al, 2001;Hergovich et al, 2003;Kuznetsova et al, 2003;Young et al, 2008).As yet, the role of VHL in maintaining normal behavior of renal epithelial cells is not clear and how VHL loss-of-function would initiate the process that leads to malignant trans- formation is incompletely understood. Recently compelling evidence has emerged for a role of VHL in maintaining expression of the AJ component E-cadherin (Esteban et al, 2006b;Krishnamachary et al, 2006;Evans et al, 2007).…”

mentioning

confidence: 99%

Regulation of Renal Epithelial Tight Junctions by the von Hippel-Lindau Tumor Suppressor Gene Involves Occludin and Claudin 1 and Is Independent of E-Cadherin

Harten

Shukla

Barod

et al. 2009

MBoC

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Epithelial-to-mesenchymal transitions (EMT) are important in renal development, fibrosis, and cancer. Loss of function of the tumor suppressor VHL leads to many features of EMT, and it has been hypothesized that the pivotal mediator is down-regulation of the adherens junction (AJ) protein E-cadherin. Here we show that VHL loss-of-function also has striking effects on the expression of the tight junction (TJ) components occludin and claudin 1 in vitro in VHL-defective clear cell renal cell carcinoma (CCRCC) cells and in vivo in VHL-defective sporadic CCRCCs (compared with normal kidney). Occludin is also down-regulated in premalignant foci in kidneys from patients with germline VHL mutations, consistent with a contribution to CCRCC initiation. Reexpression of E-cadherin was sufficient to restore AJ but not TJ assembly, indicating that the TJ defect is independent of E-cadherin down-regulation. Additional experiments show that activation of hypoxia inducible factor (HIF) contributes to both TJ and AJ abnormalities, thus the VHL/HIF pathway contributes to multiple aspects of the EMT phenotype that are not interdependent. Despite the independent nature of the defects, we show that treatment with the histone deacetylase inhibitor sodium butyrate, which suppresses HIF activation, provides a method for reversing EMT in the context of VHL inactivation. INTRODUCTIONA key characteristic of epithelial surfaces is the formation of specialized intercellular junctions at points of cell-cell contact. It is increasingly appreciated that these junctions have extensive roles beyond their function in cellular cohesion including determination of epithelial permeability and providing inputs modulating proliferation and differentiation. Two important types of intercellular junctions in the kidney epithelium are the tight junction (TJ) and adherens junction (AJ; Tsukita et al., 2001;Conacci-Sorrell et al., 2002;Matter and Balda, 2003). AJs are formed on the basolateral cell membrane and are composed of transmembrane cadherins linked to intracellular catenin proteins (Conacci-Sorrell et al., 2002). AJs are involved in cell-cell adhesion and also regulate ␤-catenin availability (Nelson and Nusse, 2004). TJs are formed on the apical surface of the lateral membrane and are analagous in structure to AJs, with specific transmembrane proteins (occludin and claudins), which are linked to the actin cytoskeleton via intracellular adaptor proteins, the zona occludens (ZO) family of proteins (Tsukita et al., 2001). In addition to its traditional roles in maintaining apical-basal polarity and controlling paracellular permeability the TJ is also now recognized as a signaling hub. TJ regulation of pathways involving raf kinase, rho GTPase, and the Y-box transcription factor ZONAB control important cellular processes such as cell proliferation, gene transcription, and cellular differentiation (Braga, 2002;Matter and Balda, 2003;Gonzalez-Mariscal et al., 2007;Guillemot et al., 2008).VHL is a classical tumor suppressor gene which acts as a gatekeeper i...

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von Hippel–Lindau protein binds hyperphosphorylated large subunit of RNA polymerase II through a proline hydroxylation motif and targets it for ubiquitination

Cited by 213 publications

References 46 publications

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

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

Interaction of Hydroxylated Collagen IV with the von Hippel-Lindau Tumor Suppressor

Regulation of Renal Epithelial Tight Junctions by the von Hippel-Lindau Tumor Suppressor Gene Involves Occludin and Claudin 1 and Is Independent of E-Cadherin

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