57646

USP28

ubiquitin specific peptidase 28;USP28;ubiquitin specific peptidase 28

deubiquitinating enzyme 28|ubiquitin carboxyl-terminal hydrolase 28|ubiquitin carboxyl-terminal hydrolase 28 variant 1|ubiquitin specific protease 28|ubiquitin thioesterase 28|ubiquitin thiolesterase 28|ubiquitin-specific-processing protease 28

11q23

protein-coding

The hypoxia-inducible transcription factor-1alpha (HIF-1alpha) 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-1alpha 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-1alpha 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-3beta and Fbw7-deficient cells revealed that GSK-3beta and Fbw7-dependent HIF-1alpha 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-1alpha-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-1alpha-dependent processes like angiogenesis and metastasis.