title: GSK-3β regulates cell growth, migration, and angiogenesis via Fbw7 and USP28-dependent degradation of HIF-1α.
abstract: 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.
authors.affiliation: Department of Biochemistry and Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Flügel
authors.forename: Agnes
authors.initials: A
authors.lastname: Görlach
authors.forename: Thomas
authors.initials: T
authors.lastname: Kietzmann
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism* / Q000502:physiology; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation; D044783:F-Box Proteins / Q000378:metabolism* / Q000502:physiology; D000073979:F-Box-WD Repeat-Containing Protein 7; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000235:genetics*; D011499:Protein Processing, Post-Translational / Q000235:genetics; D059748:Proteolysis; D015398:Signal Transduction / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000378:metabolism* / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism* / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C442902:USP28 protein, human; D044767:Ubiquitin-Protein Ligases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D043222:Ubiquitin Thiolesterase