Regulated expression of the α isoform of the human thromboxane A2 receptor during megakaryocyte differentiation : a coordinated role for WT1, Egr1 & Sp1

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dc.contributor.author Gannon, AnneMarie
dc.contributor.author Turner, Elizebeth C.
dc.contributor.author Reid, Helen M.
dc.contributor.author Kinsella, B. Therese
dc.date.accessioned 2011-09-22T15:15:25Z
dc.date.available 2011-09-22T15:15:25Z
dc.date.copyright 2009 Elsevier Ltd. en
dc.date.issued 2009-11-20
dc.identifier.citation Journal of Molecular Biology en
dc.identifier.issn 0022-2836
dc.identifier.uri http://hdl.handle.net/10197/3166
dc.description.abstract Thromboxane plays an essential role in haemostasis, regulating platelet aggregation and vessel tone. In humans, it signals through the TPalpha and TPbeta isoforms that are transcriptionally regulated by distinct promoters, Prm1 and Prm3, respectively. Herein, the consequence of megakaryocytic differentiation on Prm1-directed TPα expression was investigated. Phorbol ester (PMA) treatment substantially increased TPα mRNA and Prm1-directed gene expression in human erythroleukemia (HEL) and K562 cells. Deletional analyses localized the major responsive element(s) to the upstream -8500 and -7504 region while mutation of four WT1/Egr1/Sp1 cis-elements therein established that each contribute to the induction. Moreover, PMA increased Egr1, but not WT1 or Sp1, expression while the NAB1 co-repressor impaired PMA-induction of Egr1 and Prm1-directed gene expression. Chromatin immunoprecipitations established that WT1 is predominantly bound in vivo to the 5’ Prm1 region in non-differentiated HEL cells. In response to PMA, there was initial induction in Egr1 and associated reduction in WT1 binding to Prm1 in vivo which was displaced by Sp1 following sustained treatment. Collectively, data establish that regulated WT1 followed by sequential Egr1 and Sp1 binding to elements within Prm1 mediate repression and subsequent induction of TPα during differentiation into the megakaryocytic phenotype, shedding significant insights into factors regulating TPa expression therein. en
dc.description.sponsorship Science Foundation Ireland en
dc.description.sponsorship Health Research Board en
dc.description.sponsorship Other funder en
dc.format.extent 1494720 bytes
dc.format.mimetype application/pdf
dc.language.iso en en
dc.publisher Elsevier en
dc.relation.requires Biomolecular and Biomedical Science Research Collection en
dc.relation.requires Conway Institute Research Collection en
dc.rights This is the author’s version of a work that was accepted for publication in Journal of Molecular Biology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of Molecular Biology, 394 (1): 29-45 DOI 10.1016/j.jmb.2010.01.010. en
dc.subject Thromboxane receptor en
dc.subject Megakaryocytic differentiation en
dc.subject WT1 en
dc.subject Egr1 en
dc.subject Sp1 en
dc.subject Transcription en
dc.subject Gene en
dc.subject.lcsh Thromboxanes en
dc.subject.lcsh Megakaryocytes--Differentiation en
dc.subject.mesh Receptors, Thromboxane A2, Prostaglandin H2 en
dc.subject.mesh Cell Differentiation en
dc.subject.mesh Megakaryocytes en
dc.title Regulated expression of the α isoform of the human thromboxane A2 receptor during megakaryocyte differentiation : a coordinated role for WT1, Egr1 & Sp1 en
dc.title.alternative Thromboxane A2 receptor gene regulation en
dc.type Journal Article en
dc.internal.availability Full text available en
dc.internal.webversions Publisher's version en
dc.internal.webversions http://dx.doi.org/10.1016/j.jmb.2009.09.007 en
dc.status Peer reviewed en
dc.identifier.volume 394 en
dc.identifier.issue 1 en
dc.identifier.startpage 29 en
dc.identifier.endpage 45 en
dc.identifier.doi 10.1016/j.jmb.2009.09.007
dc.neeo.contributor Gannon|AnneMarie|aut| en
dc.neeo.contributor Turner|Elizebeth C.|aut| en
dc.neeo.contributor Reid|Helen M.|aut| en
dc.neeo.contributor Kinsella|B. Therese|aut| en
dc.description.othersponsorship Wellcome Trust en
dc.description.admin ti,ot,ke,ab,-SB02/09/2011 en


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