Cooperative Interaction of Hypoxia-inducible Factor-2α (HIF-2α) and Ets-1 in the Transcriptional Activation of Vascular Endothelial Growth Factor Receptor-2 (Flk-1)

Elvert, Gerd; Kappel, Andreas; Heidenreich, Regina; Englmeier, Ursula; Lanz, Stephan; Acker, Till; Rauter, Manuel; Plate, Karl H.; Sieweke, Michael H.; Breier, Georg; Flamme, Ingo

doi:10.1074/jbc.m211298200

Cited by 260 publications

(225 citation statements)

References 64 publications

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“…With respect to an important role in angiogenesis, we selected VEGF receptors and angiopoietins. VEGFR2, or Flk-1 and angiopoietin-2 have been described as ETS-1 target genes (Elvert et al, 2003;Hasegawa et al, 2004), whereas angiopoietin-1 is stimulated by ESE-1 from the group of ETS transcription factors, but not by ETS-1 (Brown et al, 2004). In agreement with this, we detected a downregulation of angiopoietin-2 and VEGFR2, but not of angiopoietin-1 in WT1-silenced endothelial cells.…”

Section: Wt1 Activates Ets-1 In Endothelial Cellssupporting

confidence: 89%

“…In transient transfection experiments, deletion of the identified binding site abolished activation of the ETS-1 promoter by the WT1(ÀKTS) splice variant (Figure 7d). Since angiopoietin-2 (Hasegawa et al, 2004) and the vascular endothelial growth factor receptor 2 (VEGFR2) (Elvert et al, 2003), but not angiopoietin-1 (Brown et al, 2004), have been described as a transcriptional targets of ETS-1, we analysed the expression of angiopoietin-1 and -2, and VEGFR2 in WT1-silenced cells, which show reduced levels of ETS-1 protein. Indeed, angiopoietin-2 and VEGFR2 expression levels were lower in WT1-silenced cells compared to controls whereas angiopoietin-1 was unchanged (Figure 7e).…”

Section: The Ets-1 Transcription Factor Is Regulated By Wt1mentioning

confidence: 99%

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The Wilms' tumour suppressor WT1 is involved in endothelial cell proliferation and migration: expression in tumour vessels in vivo

Wagner

Schedl

et al. 2008

Oncogene

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Vascularization is an important step in tumour growth. Although a variety of molecules, for example, VEGF, ETS-1 or nestin have been implicated in tumour angiogenesis, the molecular mechanisms of vessel formation are not fully characterized. We showed that the Wilms' tumour suppressor WT1 activates nestin during development. Here we tested whether WT1 might also be involved in tumour angiogenesis. Endothelial WT1 expression was detected in 95% of 113 tumours of different origin. To analyse the function of WT1 in endothelial cells, we used an RNAi approach in vitro and showed that inhibition of WT1 reduces cell proliferation, migration and endothelial tube formation. On a molecular level, WT1 silencing diminished expression of the ETS-1 transcription factor. WT1 and ETS-1 shared an overlapping expression in tumour endothelia. The ETS-1 promoter was stimulated approximately 10-fold by transient co-transfection of a WT1 expression construct and WT1 bound to the ETS-1 promoter in chromatin immunoprecipitation and electrophoretic mobility shift assays. Deletion of the identified WT1-binding site abolished stimulation of the ETS-1 promoter by WT1. These findings suggest that transcriptional activation of ETS-1 by the Wilms' tumour suppressor WT1 is a crucial step in tumour vascularization via regulation of endothelial cell proliferation and migration.

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Section: Wt1 Activates Ets-1 In Endothelial Cellssupporting

confidence: 89%

Section: The Ets-1 Transcription Factor Is Regulated By Wt1mentioning

confidence: 99%

The Wilms' tumour suppressor WT1 is involved in endothelial cell proliferation and migration: expression in tumour vessels in vivo

Wagner

Schedl

et al. 2008

Oncogene

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“…61 Also, the transcription factor Ets1 has been demonstrated to interact specifically with HIF-2a for the transcription of vascular endothelial growth factor (VEGF) receptor 2 , or Flk1. 62 Examples of accessory transcription molecules that are required for or enhance transcription of specific target genes include hepatocyte nuclear factor 4 (HNF-4) and Smad3. HNF-4 is a liver-and kidney-specific transcription factor reported to be required for EPO transcription at hypoxia via binding to two adjacent repeats of the HNF-4 element in close proximity to the HRE present in the EPO enhancer.…”

Section: Other Modifications Affecting Hif-driven Transcriptionmentioning

confidence: 99%

Turn me on: regulating HIF transcriptional activity

2008

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The hypoxia-inducible factors (HIFs) are critical for cellular adaptation to limiting oxygen and regulate a wide array of genes when cued by cellular oxygen-sensing mechanisms. HIF is able to direct transcription from either of two transactivation domains, each of which is regulated by distinct mechanisms. The oxygen-dependent asparaginyl hydroxylase factor-inhibiting HIF-1a (FIH-1) is a key regulator of the HIF C-terminal transactivation domain, and provides a direct link between oxygen sensation and HIFmediated transcription. Additionally, there are phosphorylation and nitrosylation events reported to modulate HIF transcriptional activity, as well as numerous transcriptional coactivators and other interacting proteins that together provide cell and tissue specificity of HIF target gene regulation. The maintenance of oxygen homeostasis is a crucial physiological requirement that involves coordinated regulation of a plethora of genes. The hypoxia-inducible transcription factors (HIFs) are responsible for a major genomic response to hypoxia, where cellular oxygen demand exceeds supply. The HIFs directly regulate the transcription of more than 70 genes involved in cellular processes that act to directly address this deficit by decreasing oxygen dependence and consumption by cells, and by increasing the efficiency of oxygen delivery to cells. These processes include vasculogenesis and angiogenesis, metabolism, vasodilation, cell migration, signalling and cell fate decisions. As such, the HIFs are fundamental to embryonic development and the pathophysiology of many serious human diseases, and are therefore subject to strict regulatory mechanisms that act to limit transcriptional activity to periods of cellular oxygen stress. The HIF proteins are subject to oxygen-dependent regulation, both at the level of protein stability (reviewed in this issue by R Bruick) and transcriptional activity, rendering them almost inactive at normoxia, but potently inducible in hypoxia. The regulation of the transcriptional activity of the HIF proteins, both via oxygen-dependent and oxygen-independent mechanisms, will be discussed in this review. The HIFsHIF is assembled from a-and b-subunits to become a transcriptionally active heterodimer. 1 Both subunits are members of the bHLH/PAS (basic helix-loop-helix/Per-ArntSim homology) family of transcription factors, and both contain transactivation domains (Figure 1). 2,3 Whereas HIF1b, also known as the aryl hydrocarbon receptor nuclear translocator (Arnt1), is a constitutively expressed nuclear protein, the a-subunit is strictly regulated in an oxygendependent manner. There are three paralogues of the HIF-a subunit, HIF-1a, HIF-2a and HIF-3a, and three paralogues of HIF-1b (Arnt1, Arnt2 and Arnt3), with either HIF-1a or HIF-2a being able to heterodimerize with HIF-1b to form the functional HIF transcription factor complexes responsible for the hypoxic shift in gene expression. HIF-3a has no known role as an active transcription factor, and is instead postulated to behave as a negative reg...

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“…Target gene specificity in this case likely arises from additional trans-acting factors and/or cis-regulatory elements that cooperate specifically with HIF-2a. In a variety of HIF-2a-selective promoters (including the WISP2 promoter) HREs have previously been reported to cooperate with ETS-family transcription factor-binding sites (Elvert et al, 2003;Aprelikova et al, 2006;Hu et al, 2007;Le Bras et al, 2007;Wang et al, 2010), and HIF-2a has been shown to physically interact with ETS-1 and ELK-1 (Elvert et al, 2003;Aprelikova et al, 2006). Other HIF-2a-regulated genes at least contained one consensus HRE (Covello et al, 2006;Yamashita et al, 2008;Yang et al, 2010), although the stringency with which the core HRE has been determined was sometimes lowered to only half-sites of the 5 0 -RCGTG-3 0 motif (Saito et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

et al. 2011

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Tumor progression is intrinsically tied to the clonal selection of tumor cells with acquired phenotypes allowing to cope with a hostile microenvironment. Hypoxiainducible factors (HIFs) master the transcriptional response to local tissue hypoxia, a hallmark of solid tumors. Here, we report significantly longer patient survival in breast cancer with high levels of HIF-2a. Amphiregulin (AREG) and WNT1-inducible signaling pathway protein-2 (WISP2) expression was strongly HIF2a-dependent and their promoters were particularly responsive to HIF-2a. The endogenous AREG promoter recruited HIF-2a in the absence of a classical HIF-DNA interaction motif, revealing a novel mechanism of gene regulation. Loss of AREG expression in HIF-2a-depleted cells was accompanied by reduced activation of epidermal growth factor (EGF) receptor family members. Apparently opposing results from patient and in vitro data point to an HIF-2a-dependent auto-stimulatory tumor phenotype that, while promoting EGF signaling in cellular models, increased the survival of diagnosed and treated human patients. Our findings suggest a model where HIF2a-mediated autocrine growth signaling in breast cancer sustains a state of cellular self-sufficiency, thereby masking unfavorable microenvironmental growth conditions, limiting adverse selection and improving therapy efficacy. Importantly, HIF-2a/AREG/WISP2-expressing tumors were associated with luminal tumor differentiation, indicative of a better response to classical treatments. Shifting the HIF-1/2a balance toward an HIF-2-dominated phenotype could thus offer a novel approach in breast cancer therapy.

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Cooperative Interaction of Hypoxia-inducible Factor-2α (HIF-2α) and Ets-1 in the Transcriptional Activation of Vascular Endothelial Growth Factor Receptor-2 (Flk-1)

Abstract: Interactions between Ets family members and a vari-

Cited by 260 publications

References 64 publications

The Wilms' tumour suppressor WT1 is involved in endothelial cell proliferation and migration: expression in tumour vessels in vivo

The Wilms' tumour suppressor WT1 is involved in endothelial cell proliferation and migration: expression in tumour vessels in vivo

Turn me on: regulating HIF transcriptional activity

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

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