| GSK-3β regulates cell growth, migration, and angiogenesis via Fbw7 and USP28-dependent degradation of HIF-1α. | |
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MedLine Citation:
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PMID: 22144179 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The hypoxia-inducible transcription factor-1α (HIF-1α) is a major regulator of angiogenesis, carcinogenesis, and various processes by which cells adapt to hypoxic conditions. Therefore, the identification of critical players regulating HIF-1α is not only important for the understanding of angiogenesis and different cancer phenotypes, but also for unraveling new therapeutic options. We report a novel mechanism by which HIF-1α is degraded after glycogen synthase kinase-3 (GSK-3)-induced phosphorylation and recruitment of the ubiquitin ligase and tumor suppressor F-box and WD protein Fbw7. Further, experiments with GSK-3β and Fbw7-deficient cells revealed that GSK-3β and Fbw7-dependent HIF-1α degradation can be antagonized by ubiquitin-specific protease 28 (USP28). In agreement with this, Fbw7 and USP28 reciprocally regulated cell migration and angiogenesis in an HIF-1α-dependent manner. Therefore, we have identified a new pathway that could be targeted at the level of GSK-3, Fbw7, or USP28 to influence HIF-1α-dependent processes like angiogenesis and metastasis. |
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Authors:
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Daniela Flügel; Agnes Görlach; Thomas Kietzmann |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2011-12-05 |
Journal Detail:
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Title: Blood Volume: 119 ISSN: 1528-0020 ISO Abbreviation: Blood Publication Date: 2012 Feb |
Date Detail:
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Created Date: 2012-02-06 Completed Date: 2012-04-05 Revised Date: 2013-04-08 |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: United States |
Other Details:
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Languages: eng Pagination: 1292-301 Citation Subset: AIM; IM |
Affiliation:
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Department of Biochemistry and Biocenter Oulu, University of Oulu, Oulu, Finland. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Cell Cycle Proteins
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metabolism*,
physiology Cell Movement / genetics* Cell Proliferation* F-Box Proteins / metabolism*, physiology Glycogen Synthase Kinase 3 / genetics, physiology* HCT116 Cells HEK293 Cells HeLa Cells Hep G2 Cells Humans Hypoxia-Inducible Factor 1, alpha Subunit / metabolism* Neovascularization, Physiologic / genetics* Protein Processing, Post-Translational / genetics Proteolysis Signal Transduction / genetics Ubiquitin Thiolesterase / metabolism*, physiology Ubiquitin-Protein Ligases / metabolism*, physiology |
| Chemical | |
Reg. No./Substance:
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0/Cell Cycle Proteins; 0/F-Box Proteins; 0/HIF1A protein, human; 0/Hypoxia-Inducible Factor 1, alpha Subunit; EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.26/Glycogen Synthase Kinase 3; EC 3.1.2.15/USP28 protein, human; EC 3.1.2.15/Ubiquitin Thiolesterase; EC 6.3.2.19/FBXW7 protein, human; EC 6.3.2.19/Ubiquitin-Protein Ligases |
| Comments/Corrections | |
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