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Calcineurin promotes hypoxia-inducible factor 1alpha expression by dephosphorylating RACK1 and blocking RACK1 dimerization.

Oxygen homeostasis represents an essential organizing principle of metazoan evolution and biology. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of transcriptional responses to changes in O2 concentration. HIF-1 is a heterodimer of HIF-1alpha and HIF-1beta subunits. O2-dependent degradation of the HIF-1alpha subunit is mediated by prolyl hydroxylase, von Hippel-Lindau protein (VHL)/Elongin-C E3 ubiquitin ligase, and the proteasome. O2-independent degradation of HIF-1alpha is regulated by the competition of RACK1 and HSP90 for binding to HIF-1alpha. RACK1 binding results in the recruitment of the Elongin-C E3 ubiquitin ligase, leading to VHL-independent ubiquitination and degradation of HIF-1alpha. In this report, we show that calcineurin inhibits the ubiquitination and proteasomal degradation of HIF-1alpha. Calcineurin is a serine/threonine phosphatase that is activated by calcium and calmodulin. The phosphatase activity of calcineurin is required for its regulation of HIF-1alpha. RACK1 binds to the catalytic domain of calcineurin and is required for HIF-1alpha degradation induced by the calcineurin inhibitor cyclosporine A. Elongin-C and HIF-1alpha each bind to RACK1 and dimerization of RACK1 is required to recruit Elongin-C to HIF-1alpha. Phosphorylation of RACK1 promotes its dimerization and dephosphorylation by calcineurin inhibits dimerization. Serine 146 within the dimerization domain is phosphorylated and mutation of serine 146 impairs RACK1 dimerization and HIF-1alpha degradation. These results indicate that intracellular calcium levels can regulate HIF-1alpha expression by modulating calcineurin activity and RACK1 dimerization.

Pubmed ID: 17965024 RIS Download

Mesh terms: Aryl Hydrocarbon Receptor Nuclear Translocator | Calcineurin | Calcium | Calmodulin | Cell Line | Cyclosporine | Dimerization | Enzyme Activation | Enzyme Inhibitors | GTP-Binding Proteins | Gene Expression Regulation | HSP90 Heat-Shock Proteins | Humans | Hypoxia-Inducible Factor 1, alpha Subunit | Neoplasm Proteins | Oxygen | Oxygen Consumption | Phosphorylation | Proteasome Endopeptidase Complex | Protein Binding | Protein Structure, Tertiary | Receptors, Cell Surface | Transcription Factors | Ubiquitin | Ubiquitin-Protein Ligases | Ubiquitination | Von Hippel-Lindau Tumor Suppressor Protein

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Associated grants

  • Agency: NHLBI NIH HHS, Id: N01 HV028180
  • Agency: NHLBI NIH HHS, Id: N01HV28180
  • Agency: NHLBI NIH HHS, Id: N01-HV28180

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