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The ?3-integrin binding protein ?3-endonexin is a novel negative regulator of hypoxia-inducible factor-1.

ABSTRACT: Integrins are multifunctional heterodimeric adhesion receptors that mediate the attachment between a cell and the extracellular matrix or other surrounding cells. In endothelial cells, integrins can modulate cell migration and motility. In particular, ?3-integrin is expressed in angiogenic vessels. Signal transduction by ?3-integrins requires the recruitment of intracellular signaling molecules. ?3-endonexin is a highly spliced molecule that has been identified as a ?3-integrin binding protein. ?3-endonexin isoforms are expressed in endothelial cells and have been suggested to act as shuttle proteins between the membrane and the nucleus. However, their functional role in angiogenesis is unclear. In this study, we investigated whether ?3-endonexin isoforms are involved in endothelial angiogenic processes under hypoxia.The overexpression of ?3-endonexin isoforms decreased endothelial proliferation and tube formation under hypoxia, while the depletion of ?3-endonexin by RNAi promoted angiogenic responses in vitro and in vivo. In hypoxia, ?3-endonexin accumulated in the nucleus, and prevention of this response by depletion of ?3-endonexin increased hypoxic activation and induction of the hypoxia-inducible factor (HIF)-1 and its target genes VEGF and PAI-1. ?3-endonexin diminished nuclear factor kappa B (NF?B) activation and decreased NF?B binding to the HIF-1? promoter under hypoxia, subsequently diminishing NF?B-dependent transcription of HIF-1? under hypoxia.Our results indicate for the first time that the overexpression of ?3-endonexin can decrease hypoxic induction and activation of HIF-1? and can prevent hypoxic endothelial proliferation and angiogenic responses.?3-endonexin can act as a novel anti-angiogenic factor specifically in the response to hypoxia due to its negative impact on the activation of HIF-1.

SUBMITTER: Kracun D

PROVIDER: S-EPMC3993052 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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The β3-integrin binding protein β3-endonexin is a novel negative regulator of hypoxia-inducible factor-1.

Kračun Damir D Riess Florian F Kanchev Ivan I Gawaz Meinrad M Görlach Agnes A

Antioxidants & redox signaling 20140313 13

<h4>Aims</h4>Integrins are multifunctional heterodimeric adhesion receptors that mediate the attachment between a cell and the extracellular matrix or other surrounding cells. In endothelial cells, integrins can modulate cell migration and motility. In particular, β3-integrin is expressed in angiogenic vessels. Signal transduction by β3-integrins requires the recruitment of intracellular signaling molecules. β3-endonexin is a highly spliced molecule that has been identified as a β3-integrin bind ...[more]

PMID: 24386901

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Project description:AimsHypoxia-inducible factor-1 alpha (HIF-1α) is a key transcription factor responsible for the induction of genes that facilitate adaptation to hypoxia. To study HIF-1 signalling in the heart, we developed a mouse model in which an oxygen-stable form of HIF-1α can be inducibly expressed in cardiac myocytes, under the regulation of tetracycline.Methods and resultsRemarkably, expression of the transgene in mice generated two distinct phenotypes. One was the expected expression of HIF-regulated transcripts and associated changes in cardiac angiogenesis and contractility. The other was an unresponsive phenotype with much less expression of typical HIF-response genes and substantial expression of a zinc-finger protein, Protein Kinase C Binding Protein 1 (PRKCBP1). We have demonstrated that this second phenotype is due to an insertion of a fragment of DNA upstream of the PRKCBP1 gene that contains two additional canonical HIF binding sites and leads to substantial HIF binding, assessed by chromatin immunoprecipitation, and transcriptional activation. This insertion is found only in the FVB strain of mice that contributed the αMHC-tet binding protein transgene to these biallelic mice. In HEK293 cells transfected with oxygen-stable HIF-1α and PRKCBP1, we demonstrated inhibition of HIF-1 activity by a luciferase reporter assay. Using mouse primary cells and cell lines, we show that transfection with oxygen-stable HIF-1α and PRKCBP1 reduced expression of direct HIF-1 gene targets and that knockdown of PRKCBP1 removes that negative inhibition. Consistent with previous reports suggesting that PRKCBP1 modulates the chromatin landscape, we found that HL-1 cells transfected with oxygen-stable HIF-1α and PRKCBP1 have reduced global 5-methyl cytosine compared to HIF-1 alone.ConclusionWe show genetic, transcriptional, biochemical, and physiological evidence that PRKCBP1 inhibits HIF activity. Identification of a new oxygen-dependent and previously unsuspected regulator of HIF may provide a target for new therapeutic approaches to ischaemic heart disease.

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The ?3-integrin binding protein ?3-endonexin is a novel negative regulator of hypoxia-inducible factor-1.

Publications

The β3-integrin binding protein β3-endonexin is a novel negative regulator of hypoxia-inducible factor-1.

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