Document Detail

GSK-3β regulates cell growth, migration, and angiogenesis via Fbw7 and USP28-dependent degradation of HIF-1α.
MedLine Citation:
PMID:  22144179     Owner:  NLM     Status:  MEDLINE    
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.
Daniela Flügel; Agnes Görlach; Thomas Kietzmann
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-12-05
Journal Detail:
Title:  Blood     Volume:  119     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-02-06     Completed Date:  2012-04-05     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1292-301     Citation Subset:  AIM; IM    
Department of Biochemistry and Biocenter Oulu, University of Oulu, Oulu, Finland.
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MeSH Terms
Cell Cycle Proteins / 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
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Neovascularization, Physiologic / genetics*
Protein Processing, Post-Translational / genetics
Signal Transduction / genetics
Ubiquitin Thiolesterase / metabolism*,  physiology
Ubiquitin-Protein Ligases / metabolism*,  physiology
Reg. No./Substance:
0/Cell Cycle Proteins; 0/F-Box Proteins; 0/HIF1A protein, human; 0/Hypoxia-Inducible Factor 1, alpha Subunit; EC synthase kinase 3 beta; EC Synthase Kinase 3; EC protein, human; EC Thiolesterase; EC protein, human; EC Ligases

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