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Hypoxia-inducible factor-1alpha obstructs a Wnt signaling pathway by inhibiting the hARD1-mediated activation of beta-catenin

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dc.contributor.authorLim, Ji-Hong-
dc.contributor.authorChun, Yang-Sook-
dc.contributor.authorPark, Jong-Wan-
dc.date.accessioned2010-07-01T07:11:35Z-
dc.date.available2010-07-01T07:11:35Z-
dc.date.issued2008-07-03-
dc.identifier.citationCancer Res. 2008;68(13):5177-5184en
dc.identifier.issn1538-7445 (Electronic)-
dc.identifier.urihttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18593917-
dc.identifier.urihttp://cancerres.aacrjournals.org/cgi/reprint/68/13/5177.pdf-
dc.identifier.urihttp://hdl.handle.net/10371/68165-
dc.description.abstractAlthough a splice variant of mouse mARD1s was found to acetylate and destabilize hypoxia-inducible factor-1alpha (HIF-1alpha), human hARD1 has no such activities. Nonetheless, hARD1 has been reported to bind directly with HIF-1alpha. Here, we addressed the functional significance of the hARD1-HIF-1alpha interaction. Because hARD1 acetylates and activates beta-catenin, we examined whether HIF-1alpha regulates the hARD1-mediated activation of Wnt signaling. It was found that HIF-1alpha binds hARD1 through the oxygen-dependent degradation domain and, in so doing, dissociates hARD1 from beta-catenin, which prevents beta-catenin acetylation. In LiCl-stimulated HEK293 or cancer cell lines with active Wnt signaling, beta-catenin acetylation and activity were suppressed in hypoxia, and these suppressions were mediated by HIF-1alpha. Moreover, HIF-1alpha disruption of hARD1/beta-catenin repressed TCF4 activity, resulting in c-Myc suppression and p21(cip1) induction. In addition, we confirmed that the HIF-1alpha NH(2) terminal inactivates TCF4 by directly binding beta-catenin. In conclusion, HIF-1alpha was found to inactivate the Wnt signaling by binding to hARD1 or beta-catenin, which may contribute to the hypoxia-induced growth arrest of tumor cells.en
dc.description.sponsorshipSeoul National University Hospital Research Fund grant 06-2008-
064-9 and Korea Science and Engineering Foundation grant R01-2006-000-10977-0.
en
dc.language.isoenen
dc.publisherAmerican Association for Cancer Researchen
dc.subjectAcetylationen
dc.subjectAcetyltransferases/metabolism/*physiologyen
dc.subjectCell Hypoxia/physiologyen
dc.subjectCell Proliferationen
dc.subjectCells, Cultureden
dc.subjectGene Expression Regulationen
dc.subjectHCT116 Cellsen
dc.subjectHumansen
dc.subjectHypoxia-Inducible Factor 1, alpha Subunit/metabolism/*physiologyen
dc.subjectModels, Biologicalen
dc.subjectProtein Bindingen
dc.subjectProto-Oncogene Proteins c-myc/geneticsen
dc.subjectProto-Oncogene Proteins p21(ras)/genetics/metabolismen
dc.subjectSignal Transductionen
dc.subjectTCF Transcription Factors/antagonists & inhibitors/metabolismen
dc.subjectWnt Proteins/*antagonists & inhibitorsen
dc.subjectbeta Catenin/*metabolismen
dc.titleHypoxia-inducible factor-1alpha obstructs a Wnt signaling pathway by inhibiting the hARD1-mediated activation of beta-cateninen
dc.typeArticleen
dc.contributor.AlternativeAuthor임지홍-
dc.contributor.AlternativeAuthor전양숙-
dc.contributor.AlternativeAuthor박종완-
dc.identifier.doi10.1158/0008-5472.CAN-07-6234-
Appears in Collections:
College of Medicine/School of Medicine (의과대학/대학원)Dept. of Physiology (생리학교실)Journal Papers (저널논문_생리학교실)
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