GSK-3β regulates cell growth, migration, and angiogenesis via Fbw7 and USP28-dependent degradation of HIF-1α

• Published in: Blood 2012-02, Vol.119 (5), p.1292-1301
• Main Authors: Flügel, Daniela, Görlach, Agnes, Kietzmann, Thomas
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cell Cycle Proteins - metabolism; Cell Cycle Proteins - physiology; Cell Movement - genetics; Cell Proliferation; F-Box Proteins - metabolism; F-Box Proteins - physiology; F-Box-WD Repeat-Containing Protein 7; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - physiology; Glycogen Synthase Kinase 3 beta; HCT116 Cells; HEK293 Cells; HeLa Cells; Hematologic and hematopoietic diseases; Hep G2 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Medical sciences; Neovascularization, Physiologic - genetics; Protein Processing, Post-Translational - genetics; Proteolysis; Signal Transduction - genetics; Ubiquitin Thiolesterase - metabolism; Ubiquitin Thiolesterase - physiology; Ubiquitin-Protein Ligases - metabolism; Ubiquitin-Protein Ligases - physiology; Vascular Biology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-08-375014

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.