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Hypoxic induction of the regulator of G-protein signalling 4 gene is mediated by the hypoxia-inducible factor pathway

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dc.contributor.authorOlechnowicz, S.
dc.contributor.authorFedele, A.
dc.contributor.authorPeet, D.
dc.contributor.editorDatta, K.
dc.date.issued2012
dc.description.abstractThe transcriptional response to hypoxia is largely dependent on the Hypoxia Inducible Factors (HIF-1 and HIF-2) in mammalian cells. Many target genes have been characterised for these heterodimeric transcription factors, yet there is evidence that the full range of HIF-regulated genes has not yet been described. We constructed a TetON overexpression system in the rat pheochromocytoma PC-12 cell line to search for novel HIF and hypoxia responsive genes. The Rgs4 gene encodes the Regulator of G-Protein Signalling 4 (RGS4) protein, an inhibitor of signalling from G-protein coupled receptors, and dysregulation of Rgs4 is linked to disease states such as schizophrenia and cardiomyopathy. Rgs4 was found to be responsive to HIF-2a overexpression, hypoxic treatment, and hypoxia mimetic drugs in PC-12 cells. Similar responses were observed in human neuroblastoma cell lines SK-N-SH and SK-N-BE(2)C, but not in endothelial cells, where Rgs4 transcript is readily detected but does not respond to hypoxia. Furthermore, this regulation was found to be dependent on transcription, and occurs in a manner consistent with direct HIF transactivation of Rgs4 transcription. However, no HIF binding site was detectable within 32 kb of the human Rgs4 gene locus, leading to the possibility of regulation by longdistance genomic interactions. Further research into Rgs4 regulation by hypoxia and HIF may result in better understanding of disease states such as schizophrenia, and also shed light on the other roles of HIF yet to be discovered.
dc.description.statementofresponsibilitySam W.Z. Olechnowicz, Anthony O. Fedele and Daniel J. Peet
dc.identifier.citationPLoS One, 2012; 7(9):1-12
dc.identifier.doi10.1371/journal.pone.0044564
dc.identifier.issn1932-6203
dc.identifier.issn1932-6203
dc.identifier.orcidPeet, D. [0000-0002-6085-8936]
dc.identifier.urihttp://hdl.handle.net/2440/74108
dc.language.isoen
dc.publisherPublic Library of Science
dc.rights© 2012 Olechnowicz et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.source.urihttps://doi.org/10.1371/journal.pone.0044564
dc.subjectPC12 Cells
dc.subjectAnimals
dc.subjectRats
dc.subjectDactinomycin
dc.subjectRGS Proteins
dc.subjectRNA, Small Interfering
dc.subjectDNA Primers
dc.subjectOligonucleotide Array Sequence Analysis
dc.subjectGene Expression Profiling
dc.subjectPolymerase Chain Reaction
dc.subjectBase Sequence
dc.subjectBasic Helix-Loop-Helix Transcription Factors
dc.subjectHypoxia
dc.titleHypoxic induction of the regulator of G-protein signalling 4 gene is mediated by the hypoxia-inducible factor pathway
dc.typeJournal article
pubs.publication-statusPublished

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