The contribution of VHL substrate binding and HIF1-α to the phenotype of VHL loss in renal cell carcinoma

Maranchie, Jodi K.; Vasselli, James R.; Riss, Joseph; Bonifacino, Juan S.; Linehan, W. Marston; Klausner, Richard D.

doi:10.1016/s1535-6108(02)00044-2

Cited by 419 publications

(300 citation statements)

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“…However, recent studies have revealed that in this setting, upregulation of HIF-1a and HIF-2a activates distinct target genes and has contrasting effects on the growth of tumours (Maranchie et al, 2002;Kondo et al, 2002Kondo et al, , 2003Zimmer et al, 2004;Raval et al, 2005). These findings imply that strategies for therapeutic blockade of HIF pathways for RCC should most likely attempt to be isoform specific.…”

Section: Discussionmentioning

confidence: 99%

“…They have a highly conserved domain architecture, including sites of prolyl and asparaginyl hydroxylation, and strongly promote transcription from similar hypoxia response elements (HREs). However, there is increasing evidence for the functional non-equivalence of HIF-1a and HIF-2a, and in cancer, several recent studies have indicated that, at least in certain settings, they have contrasting effects on tumour growth (Maranchie et al, 2002;Kondo et al, 2002Kondo et al, , 2003Zimmer et al, 2004;Covello et al, 2005;Raval et al, 2005). In VHL-defective renal carcinoma cells (RCC), inactivation of HIF-a proteolysis upregulates both HIF-1a and HIF-2a with global induction of HIF target gene expression (Maxwell et al, 1999), stimulating investigations of the role of the HIF pathway in tumour development (Maranchie et al, 2002;Kondo et al, 2002Kondo et al, , 2003Zimmer et al, 2004;Raval et al, 2005).…”

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confidence: 99%

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Target gene selectivity of hypoxia-inducible factor-α in renal cancer cells is conveyed by post-DNA-binding mechanisms

Lau¹,

Tian²,

Raval³

et al. 2007

Br J Cancer

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Inactivation of the von Hippel -Lindau tumour suppressor in renal cell carcinoma (RCC) leads to failure of proteolytic regulation of the a subunits of hypoxia-inducible factor (HIF), constitutive upregulation of the HIF complex, and overexpression of HIF target genes. However, recent studies have indicated that in this setting, upregulation of the closely related HIF-a isoforms, HIF-1a and HIF-2a, have contrasting effects on tumour growth, and activate distinct sets of target genes. To pursue these findings, we sought to elucidate the mechanisms underlying target gene selectivity for HIF-1a and HIF-2a. Using chromatin immunoprecipitation to probe binding to hypoxia response elements in vivo, and expression of chimaeric molecules bearing reciprocal domain exchanges between HIF-1a and HIF-2a molecules, we show that selective activation of HIF-a target gene expression is not dependent on selective DNAbinding at the target locus, but depends on non-equivalent C-terminal portions of these molecules. Our data indicate that post-DNA binding mechanisms that are dissimilar for HIF-1a and HIF-2a determine target gene selectivity in RCC cells.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Target gene selectivity of hypoxia-inducible factor-α in renal cancer cells is conveyed by post-DNA-binding mechanisms

Lau¹,

Tian²,

Raval³

et al. 2007

Br J Cancer

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“…[28][29][30] An inherited deficiency in pVHL allows HIF to become constitutively active, leading to renal cell carcinoma, further illustrating the importance of HIF in cancer pathology. 31,32 HIF is additionally hydroxylated at an asparagine residue by factor-inhibiting HIF (FIH). [33][34][35] This prevents HIF from interacting with the transcriptional coactivators p300 and CREB-binding protein (CBP), thereby reducing the transactivating activity of HIF.…”

Section: Regulation Of Hif Functionmentioning

confidence: 99%

mentioning

confidence: 99%

Mitochondrial complex III regulates hypoxic activation of HIF

2008

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Decreases in oxygen levels are observed in physiological processes, such as development, and pathological situations, such as tumorigenesis and ischemia. In the complete absence of oxygen (anoxia), mammalian cells are unable to generate sufficient energy for survival, so a mechanism for sensing a decrease in the oxygen level (hypoxia) before it reaches a critical point is crucial for the survival of the organism. In response to decreased oxygen levels, cells activate the transcription factors hypoxiainducible factors (HIFs), which lead to metabolic adaptation to hypoxia, as well as to generate new vasculature to increase oxygen supply. How cells sense decreases in oxygen levels to regulate HIF activation has been hotly debated. Emerging evidence indicates that reactive oxygen species (ROS) generated by mitochondrial complex III are required for hypoxic activation of HIF. This review examines the current knowledge about the role of mitochondrial ROS in HIF activation, as well as implications of ROS-level regulation in pathological processes such as cancer. Oxygen Homeostasis and HIF Maintaining oxygen homeostasis is critical for survival and proper function of cells and organisms. 1 Reduced oxygen levels (hypoxia) initiates proper placental and vascular development. Hypoxia also has a causal role in pathological conditions such as ischemia-related diseases and cancer. A complete absence of oxygen (anoxia) results in cell death. 2 ATP synthesis is ablated, and most cells undergo apoptosis soon after anoxia exposure. 3-5 Cells exposed to hypoxia, or reduced oxygen levels, on the other hand, are able to maintain normal ATP synthesis and survive. 5,6 However, as cells replicate in a hypoxic environment, they reduce the oxygen supply even further and generate levels of local anoxia. Therefore, cells must respond quickly to decreasing oxygen levels before reaching an anoxic state (Figure 1).Mammalian cells respond to hypoxia by activating broadaction transcription factors named hypoxia-inducible factors, or HIFs, which are expressed by virtually all cells of the body. 7-9 Three members of the HIF family exist, named HIF1, HIF2 and HIF-3. 10-13 HIFs bind to hypoxia-responsive elements, consensus sequences in the promoter region of more than one hundred genes, activating the transcription of genes that allow the cell to adapt to and survive in the hypoxic environment. 14,15 Genes regulated by HIFs include glucose transporter that allow the cells to efficiently import glucose to continue generating ATP despite reduced nutrient availability; and genes that reorganize the microenvironment to bring in oxygen, such as vascular endothelial growth factor, which stimulates formation of new blood vessels. [16][17][18] Importantly for tumorigenesis, HIF also turns on genes such as insulin-like growth factor 2,19 which induces cellular survival and proliferation, as well as those that promote tumor invasion and migration, such as matrix metalloproteinase-2. 20 These factors contribute to tumor growth and invasion and metastasis, im...

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“…The stabilized HIF-1/2α obviously accelerates blood vessel formation around tumours, explaining the mechanism of pVHL dysfunction in tumour progression. However, more evidence shows that dysregulation of HIF-1/2α is insufficient to initiate de novo tumorigenesis in VHL-deficient cells [42][43][44][45], suggesting that pVHL may have HIF-independent functions accounting for its tumour suppression. Rb was the first tumour suppressor gene identified which negatively regulates cell proliferation [32].…”

Section: Discussionmentioning

confidence: 99%

pVHL acts as a downstream target of E2F1 to suppress E2F1 activity

Wang

Zhang

et al. 2013

Biochemical Journal

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The VHL (von Hippel-Lindau) gene is a well-defined tumour suppressor linked to hereditary cancer syndromes. Although it is well documented that pVHL (von Hippel-Lindau protein) mediates HIF (hypoxia-inducible factor)-1/2α degradation under conditions of normoxia, accounting for a major mechanism of pVHL in tumour suppression, it remains elusive whether other HIF-independent functions contribute to the pVHL tumour suppressive function. In the present study, we found that pVHL is a downstream target of E2F1, which harbours an E2F1-binding site in its promoter. Moreover, pVHL binds to E2F1 in vitro and in vivo, resulting in inhibition of E2F1 transcriptional activity. Mechanistic studies showed that pVHL binding enhances E2F1 deacetylation. Further immunoprecipitation assays indicated that the pVHL interaction diminishes P/CAF [p300/CREB (cAMPresponse-element-binding protein)-binding protein-associated factor] and p300 association with E2F1, but enhances Sirt1 (sirtuin 1) binding to E2F1. In addition, upon DNA damage, pVHL is induced. Knockdown of pVHL sensitizes cells to DNA-damageinduced apoptosis dependent on E2F1, uncovering a role for pVHL in the response to DNA damage. The findings of the present study reveal a novel function of pVHL and demonstrate a negative-feedback loop between pVHL and E2F1, which may shed new light on the explanation of the role of pVHL in tumour suppression.

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The contribution of VHL substrate binding and HIF1-α to the phenotype of VHL loss in renal cell carcinoma

Cited by 419 publications

References 40 publications

Target gene selectivity of hypoxia-inducible factor-α in renal cancer cells is conveyed by post-DNA-binding mechanisms

Target gene selectivity of hypoxia-inducible factor-α in renal cancer cells is conveyed by post-DNA-binding mechanisms

Mitochondrial complex III regulates hypoxic activation of HIF

pVHL acts as a downstream target of E2F1 to suppress E2F1 activity

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