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Cancer Res. 2008 Jul 1;68(13):5177-84. doi: 10.1158/0008-5472.CAN-07-6234.

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

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  • 1Department of Pharmacology, Seoul National University College of Medicine, Chongno-gu, Seoul, Korea.

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.

PMID:
18593917
DOI:
10.1158/0008-5472.CAN-07-6234
[PubMed - indexed for MEDLINE]
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