The von Hippel-Lindau Gene Product Inhibits Vascular Permeability Factor/Vascular Endothelial Growth Factor Expression in Renal Cell Carcinoma by Blocking Protein Kinase C Pathways

Pal, Soumitro; Claffey, Kevin P.; Dvorak, Harold F.; Mukhopadhyay, Debabrata

doi:10.1074/jbc.272.44.27509

Cited by 132 publications

(91 citation statements)

References 28 publications

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“…Un-®xed cells were stained with Trypan blue to certify that most of the cells were alive (data not shown). Bars, 30 mm PKCs and the VHL protein has been reported, and is known to be involved in the regulation of cell growth or apoptosis (Okuda et al, 1999;Pal et al, 1997). VHL also acts as a Nedd8 ligase for Cul-2, which may be involved in cell cycle regulation (Feng et al, 1999;Liakopoulos et al, 1999;Wada et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Tumor suppressor protein VHL is induced at high cell density and mediates contact inhibition of cell growth

Hirai

Kawakami

et al. 2001

Oncogene

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In spite of the general recognition of von Hippel-Lindau (VHL) as a tumor suppressor gene, the physiological and pathological importance of VHL protein in cell growth regulation and tumorigenesis remains unclear. Here we show that in normal human renal proximal tubule epithelial cells (RPTEC), the steady-state amount of VHL protein is strictly regulated by cell density. The cellular VHL content is more than 100-fold higher in dense cultures than in sparse cultures. The increase in VHL protein at high cell density was also observed for NIH3T3 ®broblasts, suggesting the generality of the phenomenon. The growth rates of renal cell carcinoma cells lacking an intact VHL gene and their derivatives with wild-type or mutant VHL expression vector do not di er signi®cantly when they are growing in log-phase. Importantly, however, there is a di erence when they reach con¯uency: cells lacking wild-type VHL grew continuously, while cells expressing exogenous VHL protein showed relatively limited cell growth. Using an ecdysone-inducible VHL expressing cell line, we also show that the growth inhibition at high cell density can be released by attenuating the VHL expression. Taken together, we propose that VHL protein functions as a growth suppressor at high cell density, and this might be the basis of the tumor suppressor function of VHL.

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Section: Discussionmentioning

confidence: 99%

Tumor suppressor protein VHL is induced at high cell density and mediates contact inhibition of cell growth

Hirai

Kawakami

et al. 2001

Oncogene

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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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“…High glucose concentration has been shown to stimulate VEGF expression in vascular smooth muscle cells [137], probably through PKC stimulation [138]. In addition, phorbol esters stimulate mesangial VEGF production [139] and notably, inhibition of PKC blocks VEGF signalling [140]. Further, various growth factors and cytokines, including TGF-b [141,142], IGF-I [143], basic fibroblastic growth factor (bFGF) [144] and platelet derived growth factor (PDGF) [136,145] have been shown to stimulate VEGF production in various non-renal cell types.…”

Section: In Vitro Evidence For Vegf Effects On Kidney Cellsmentioning

confidence: 99%

Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease

2000

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The von Hippel-Lindau Gene Product Inhibits Vascular Permeability Factor/Vascular Endothelial Growth Factor Expression in Renal Cell Carcinoma by Blocking Protein Kinase C Pathways

Cited by 132 publications

References 28 publications

Tumor suppressor protein VHL is induced at high cell density and mediates contact inhibition of cell growth

Tumor suppressor protein VHL is induced at high cell density and mediates contact inhibition of cell growth

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

Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease

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