Hypoxia-induced and calpain-dependent cleavage of filamin A regulates the hypoxic response
Copyright policy )Hypoxia-induced and calpain-dependent cleavage of filamin A regulates the hypoxic response
Significance The cellular response to hypoxia is regulated by hypoxia-inducible factor-1α and -2α (HIF-1α and -2α). We have discovered that filamin A (FLNA), a large cytoskeletal actin-binding protein, physically interacts with HIF-1α (but not with HIF-2α) and promotes tumor growth and angiogenesis. Hypoxia induces a calpain-dependent cleavage of FLNA to generate a fragment that enhances nuclear accumulation of HIF-1α and is corecruited to HIF-1α target promoters, resulting in enhanced gene expression. This mechanism helps to explain why FLNA is upregulated in certain tumors and offers opportunities in targeting the hypoxia signaling pathway therapeutically.
- National University of Singapore Libraries Singapore
- Karolinska Institute Sweden
- University of Gothenburg Sweden
- National University of Singapore Singapore
Vascular Endothelial Growth Factor A, Chromatin Immunoprecipitation, Neovascularization, Pathologic, Subcellular localization, Filamins, Mice, SCID, Signal transduction, Hypoxia-Inducible Factor 1, alpha Subunit, Real-Time Polymerase Chain Reaction, Cell Hypoxia, Fluorescence, Gene Expression Regulation, Neoplastic, Mice, Basic Helix-Loop-Helix Transcription Factors, Animals, Heterografts, Immunoprecipitation, RNA Interference, Cancer
Vascular Endothelial Growth Factor A, Chromatin Immunoprecipitation, Neovascularization, Pathologic, Subcellular localization, Filamins, Mice, SCID, Signal transduction, Hypoxia-Inducible Factor 1, alpha Subunit, Real-Time Polymerase Chain Reaction, Cell Hypoxia, Fluorescence, Gene Expression Regulation, Neoplastic, Mice, Basic Helix-Loop-Helix Transcription Factors, Animals, Heterografts, Immunoprecipitation, RNA Interference, Cancer
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