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

  1. Daniela Flügel1,
  2. Agnes Görlach2, and
  3. Thomas Kietzmann1
  1. 1Department of Biochemistry and Biocenter Oulu, University of Oulu, Oulu, Finland; and
  2. 2Experimental and Molecular Pediatric Cardiology, German Heart Center Munich at the Technical University, Munich, Germany

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.

  • Submitted August 20, 2011.
  • Accepted November 30, 2011.
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