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

Cited 65 time in Web of Science Cited 69 time in Scopus
Authors
Lim, Ji-Hong; Chun, Yang-Sook; Park, Jong-Wan
Issue Date
2008-07-03
Publisher
American Association for Cancer Research
Citation
Cancer Res. 2008;68(13):5177-5184
Keywords
AcetylationAcetyltransferases/metabolism/*physiologyCell Hypoxia/physiologyCell ProliferationCells, CulturedGene Expression RegulationHCT116 CellsHumansHypoxia-Inducible Factor 1, alpha Subunit/metabolism/*physiologyModels, BiologicalProtein BindingProto-Oncogene Proteins c-myc/geneticsProto-Oncogene Proteins p21(ras)/genetics/metabolismSignal TransductionTCF Transcription Factors/antagonists & inhibitors/metabolismWnt Proteins/*antagonists & inhibitorsbeta Catenin/*metabolism
Abstract
Although 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.
ISSN
1538-7445 (Electronic)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18593917

http://cancerres.aacrjournals.org/cgi/reprint/68/13/5177.pdf

http://hdl.handle.net/10371/68165
DOI
https://doi.org/10.1158/0008-5472.CAN-07-6234
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Physiology (생리학교실)Journal Papers (저널논문_생리학교실)
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