Hypoxia Inducible Factor-2α in Cancer

Löfstedt, Tobias; Fredlund, Erik; Mengelbier, Linda Holmquist; Pietras, Alexander; Ovenberger, Marie; Poellinger, Lorenz; Påhlman, Sven

doi:10.4161/cc.6.8.4133

Cited by 174 publications

(154 citation statements)

References 84 publications

(147 reference statements)

Supporting

Mentioning

149

Contrasting

Unclassified

Order By: Relevance

“…In addition, HIF-2a (rather than HIF-1a) regulates a subset of genes involved in angiogenic responses, such as Tie-2/TEK, VEGFR1 (Flt-1), VEGFR2 (Kdr/Flk-1), VE-cadherin, EPO and TGF-a (Tian et al, 1997;Takeda et al, 2004;Elvert et al, 2003;Raval et al, 2005;Le Bras et al, 2007). Moreover, the kinetics of endosialin induction by hypoxia with a maximum level achieved during a 24 h incubation period as well as an optimal oxygen concentration between 2 and 5% (data not shown) better correspond to the temporal profile and activation optimum of HIF-2a, which increases with time at moderate-to-mild hypoxia, whereas HIF-1a stabilisation occurs at lower oxygen concentration and its levels are reduced at prolonged hypoxia (Löfstedt et al, 2007). Thus, the endosialin Empty pcDNA3.1 was used to adjust total DNA content in all samples to 3 mg.…”

Section: Discussionmentioning

confidence: 99%

“…This effect is partly related to pericellular hypoxia and as such might again involve HIF-2, the stabilisation and activation of which requires just a mild lowering of oxygen tension (Löfstedt et al, 2007). As the SP1 transcription Figure 7 Schematic illustration of the molecular anatomy of the endosialin promoter and regulatory pathways induced by hypoxia and cell density.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Hypoxia upregulates expression of human endosialin gene via hypoxia-inducible factor 2

et al. 2008

View full text Add to dashboard Cite

Endosialin is a transmembrane glycoprotein selectively expressed in blood vessels and stromal fibroblasts of various human tumours. It has been functionally implicated in angiogenesis, but the factors that control its expression have remained unclear. As insufficient delivery of oxygen is a driving force of angiogenesis in growing tumours, we investigated whether hypoxia regulates endosialin expression. Here, we demonstrate that endosialin gene transcription is induced by hypoxia predominantly through a mechanism involving hypoxia-inducible factor-2 (HIF-2) cooperating with the Ets-1 transcription factor. We show that HIF-2 activates the endosialin promoter both directly, through binding to a hypoxia-response element adjacent to an Ets-binding site in the distal part of the upstream regulatory region, and indirectly, through Ets-1 and its two cognate elements in the proximal promoter. Our data also suggest that the SP1 transcription factor mediates responsiveness of the endosialin promoter to high cell density. These findings elucidate important aspects of endosialin gene regulation and provide a rational frame for future investigations towards better understanding of its biological significance.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hypoxia upregulates expression of human endosialin gene via hypoxia-inducible factor 2

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Another interesting aspect of tumor hypoxia is the well-documented association between oxygen shortage and tumor aggressiveness (reviewed in Bertout et al 2008) . The mechanistic background is probably very complex, but involves cytotoxic resistance, insensitivity to radiation, decreased DNA repair capacity, increased vascularization and increased metastatic potential (reviewed in Semenza 2003;Erler et al 2006;Löfstedt et al 2007) and, as will be discussed in more detail below, dedifferentiation or loss of a differentiated tumor phenotype.…”

Section: Hypoxia In Solid Tumors and Relation To Tumor Aggressivenessmentioning

confidence: 99%

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

Pietras

Johnsson

Påhlman

2010

Current Topics in Microbiology and Immunology

Self Cite

View full text Add to dashboard Cite

“…Most human tumors analysed express detectable levels of HIF-1a and HIF-2a proteins, while normal tissues are generally negative, safe for macrophages (Talks et al, 2000). Further, high HIF-2a levels are correlated with advanced stage and poor patient outcome in several tumor forms (Lofstedt et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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.

show abstract

Hypoxia Inducible Factor-2α in Cancer

Cited by 174 publications

References 84 publications

Hypoxia upregulates expression of human endosialin gene via hypoxia-inducible factor 2

Hypoxia upregulates expression of human endosialin gene via hypoxia-inducible factor 2

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

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

Contact Info

Product

Resources

About