Hypoxia-inducible factor-1alpha obstructs a Wnt signaling pathway by inhibiting the hARD1-mediated activation of beta-catenin
- PMID: 18593917
- 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
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.
Similar articles
-
Vasculogenesis and angiogenesis initiation under normoxic conditions through Wnt/β-catenin pathway in gliomas.Rev Neurosci. 2018 Jan 26;29(1):71-91. doi: 10.1515/revneuro-2017-0032. Rev Neurosci. 2018. PMID: 28822229 Review.
-
The protein acetyltransferase ARD1: a novel cancer drug target?Curr Cancer Drug Targets. 2008 Nov;8(7):545-53. doi: 10.2174/156800908786241113. Curr Cancer Drug Targets. 2008. PMID: 18991565 Review.
-
Human arrest defective 1 acetylates and activates beta-catenin, promoting lung cancer cell proliferation.Cancer Res. 2006 Nov 15;66(22):10677-82. doi: 10.1158/0008-5472.CAN-06-3171. Cancer Res. 2006. PMID: 17108104
-
Purified recombinant hARD1 does not catalyse acetylation of Lys532 of HIF-1alpha fragments in vitro.FEBS Lett. 2006 Apr 3;580(8):1911-8. doi: 10.1016/j.febslet.2006.02.012. Epub 2006 Feb 17. FEBS Lett. 2006. PMID: 16500650
-
Interaction between HIF-1 alpha (ODD) and hARD1 does not induce acetylation and destabilization of HIF-1 alpha.FEBS Lett. 2005 Nov 21;579(28):6428-32. doi: 10.1016/j.febslet.2005.10.036. Epub 2005 Nov 2. FEBS Lett. 2005. PMID: 16288748 Free PMC article.
Cited by
-
Mitochondrial leak metabolism induces the Spemann-Mangold Organizer via Hif-1α in Xenopus.Dev Cell. 2023 Nov 20;58(22):2597-2613.e4. doi: 10.1016/j.devcel.2023.08.015. Epub 2023 Sep 5. Dev Cell. 2023. PMID: 37673063
-
Protein stabilization of ITF2 by NF-κB prevents colitis-associated cancer development.Nat Commun. 2023 Apr 25;14(1):2363. doi: 10.1038/s41467-023-38080-w. Nat Commun. 2023. PMID: 37185280 Free PMC article.
-
Visible light-initiated radical 1,3-difunctionalization of β,γ-unsaturated ketones.Sci Adv. 2022 Dec 9;8(49):eabq8596. doi: 10.1126/sciadv.abq8596. Epub 2022 Dec 9. Sci Adv. 2022. PMID: 36490351 Free PMC article.
-
Hypoxia is fine-tuned by Hif-1α and regulates mesendoderm differentiation through the Wnt/β-Catenin pathway.BMC Biol. 2022 Oct 5;20(1):219. doi: 10.1186/s12915-022-01423-y. BMC Biol. 2022. PMID: 36199093 Free PMC article.
-
DARS-AS1 recruits METTL3/METTL14 to bind and enhance DARS mRNA m6A modification and translation for cytoprotective autophagy in cervical cancer.RNA Biol. 2022 Jan;19(1):751-763. doi: 10.1080/15476286.2022.2079889. RNA Biol. 2022. PMID: 35638109 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
