Targeted Replacement of Hypoxia-Inducible Factor-1α by a Hypoxia-Inducible Factor-2α Knock-in Allele Promotes Tumor Growth

Covello, Kelly L.; Simon, M. Celeste; Keith, Brian

doi:10.1158/0008-5472.can-04-3246

Cited by 108 publications

(105 citation statements)

References 48 publications

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“…Although no specific HIF-2a-regulated genes were identified in these studies, other recent reports showed that HIF-2a could indeed up and downregulate a different set of genes than HIF-1a in HEK-293 cells (Wang et al, 2005) and in renal carcinoma cells (Raval et al, 2005). HIF-1a has been shown to activate specifically the glycolytic enzymes PGK and aldolase A, while Oct-4, a transcription factor involved in maintaining pluripotentiality of ES cells, appears to be regulated by HIF-2a but not by HIF-1a (Hu et al, 2003;Covello et al, 2005Covello et al, , 2006.…”

Section: Hif-2a Specifically Activates the Ve-cadherin Gene A Le Brasmentioning

confidence: 66%

HIF-2α specifically activates the VE-cadherin promoter independently of hypoxia and in synergy with Ets-1 through two essential ETS-binding sites

et al. 2007

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The mechanisms that are responsible for the restricted pattern of expression of the VE-cadherin gene in endothelial cells are not clearly understood. Regulation of expression is under the control of an approximately 140 bp proximal promoter that provides basal, nonendothelial specific expression. A larger region contained within the 2.5 kb genomic DNA sequence located ahead of the transcription start is involved in the specific expression of the gene in endothelial cells. We show here that the VE-cadherin promoter contains several putative hypoxia response elements (HRE) which are able to bind endothelial nuclear factors under normoxia. The VE-cadherin gene is not responsive to hypoxia but hypoxia-inducible factor (HIF)-2a specifically activates the promoter while HIF-1a does not. The HRE, that are involved in this activity have been identified. Further, we show that HIF2a cooperates with the Ets-1 transcription factor for activation of the VE-cadherin promoter and that this synergy is dependent on the binding of Ets-1 to DNA. This cooperative action of HIF-2a with Ets-1 most probably participates to the transcriptional regulation of expression of the gene in endothelial cells. This mechanism may also be involved in the expression of the VE-cadherin gene by tumor cells in the process of vascular mimicry.

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Section: Hif-2a Specifically Activates the Ve-cadherin Gene A Le Brasmentioning

confidence: 66%

HIF-2α specifically activates the VE-cadherin promoter independently of hypoxia and in synergy with Ets-1 through two essential ETS-binding sites

et al. 2007

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“…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).…”

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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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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“…However, evidence has recently accumulated that the role of HIFs in oncogenesis is more complicated and may depend on cell types and specific settings. One striking example is HIF-2a, the protein that is absolutely required for tumor formation of RCCs with the inactivation of VHL while it acts as a tumor suppressor in malignant gliomas (19,21,(32)(33)(34). Interestingly, the effect of HIF-1a and HIF-2a on certain target gene expression has been shown to differ completely between RCC cells and other types of cancer cells (17).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it is likely that HIF-2a -mediated inhibition of hTERT expression may directly or indirectly contribute to apoptosis occurring in HIF-2a -overexpressing glioma cells. On the other hand, RCC cells with VHL inactivation require HIF-2a for their oncogenesis (21,(32)(33)(34). Given an essential role for telomerase in cell immortalization and transformation (1, 2), it seems reasonable that HIF-2a induces rather than inhibits hTERT expression in RCC cells.…”

Section: Discussionmentioning

confidence: 99%

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The Opposing Effect of Hypoxia-Inducible Factor-2α on Expression of Telomerase Reverse Transcriptase

Lou¹,

Chen

Jalink

et al. 2007

Molecular Cancer Research

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Hypoxia-inducible factor-1A (HIF-1A) has been implicated in the transcriptional regulation of the telomerase reverse transcriptase (hTERT) gene expression and telomerase activity, essential elements for cellular immortalization and transformation. However, controversial results were obtained in different studies. Moreover, it is totally unclear whether HIF-2A, the paralog of HIF-1A, plays a role in regulating hTERT expression. In the present study, we found that hypoxic treatment enhanced hTERT mRNA expression and telomerase activity in three renal cell carcinoma (RCC) cell lines with different genetic backgrounds. Both HIF-1A and HIF-2A were capable of significantly increasing the hTERT promoter activity in these cells. Moreover, depleting HIF-2A led to a down-regulation of hTERT mRNA level in RCC A498 cells expressing constitutive HIF-2A. It was found that HIF-2A bound to the hTERT proximal promoter and enhanced the recruitment of the histone acetyltransferase p300 and histone H3 acetylation locally in A498 cells treated with hypoxia. Increased levels of hTERT mRNA were observed in two of three hypoxia-treated malignant glioma cell lines. However, HIF-1A stimulated whereas HIF-2A inhibited the hTERT promoter activity in these glioma cell lines. Ectopic expression of HIF-2A resulted in diminished hTERT expression in glioma cells. Collectively, HIF-1A activates hTERT and telomerase expression in both RCC and glioma cells, and HIF-2A enhances hTERT expression in RCC cells, whereas it represses the hTERT transcription in glioma cells.

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Targeted Replacement of Hypoxia-Inducible Factor-1α by a Hypoxia-Inducible Factor-2α Knock-in Allele Promotes Tumor Growth

Cited by 108 publications

References 48 publications

HIF-2α specifically activates the VE-cadherin promoter independently of hypoxia and in synergy with Ets-1 through two essential ETS-binding sites

HIF-2α specifically activates the VE-cadherin promoter independently of hypoxia and in synergy with Ets-1 through two essential ETS-binding sites

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

The Opposing Effect of Hypoxia-Inducible Factor-2α on Expression of Telomerase Reverse Transcriptase

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