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Hypoxia-inducible factor-1alpha obstructs a Wnt signaling pathway by inhibiting the hARD1-mediated activation of beta-catenin
Cited 74 time in
Web of Science
Cited 79 time in Scopus
- Authors
- Issue Date
- 2008-07-03
- Publisher
- American Association for Cancer Research
- Citation
- Cancer Res. 2008;68(13):5177-5184
- Keywords
- Acetylation ; Acetyltransferases/metabolism/*physiology ; Cell Hypoxia/physiology ; Cell Proliferation ; Cells, Cultured ; Gene Expression Regulation ; HCT116 Cells ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism/*physiology ; Models, Biological ; Protein Binding ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins p21(ras)/genetics/metabolism ; Signal Transduction ; TCF Transcription Factors/antagonists & inhibitors/metabolism ; Wnt Proteins/*antagonists & inhibitors ; beta 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
https://hdl.handle.net/10371/68165
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