Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha.
To survive in hypoxic environments, organisms must be able to cope with redox imbalance and oxygen deficiency. The SIRT1 deacetylase and the HIF-1alpha transcription factor act as redox and oxygen sensors, respectively. Here, we found that SIRT1 binds to HIF-1alpha and deacetylates it at Lys674, which is acetylated by PCAF. ... By doing so, SIRT1 inactivated HIF-1alpha by blocking p300 recruitment and consequently repressed HIF-1 target genes. During hypoxia, SIRT1 was downregulated due to decreased NAD(+) levels, which allowed the acetylation and activation of HIF-1alpha. Conversely, when the redox change was attenuated by blocking glycolysis, SIRT1 was upregulated, leading to the deacetylation and inactivation of HIF-1alpha even in hypoxia. In addition, we confirmed the SIRT1-HIF-1alpha interaction in hypoxic mouse tissues and observed in vivo that SIRT1 has negative effects on tumor growth and angiogenesis. Our results suggest that crosstalk between oxygen- and redox-responsive signal transducers occurs through the SIRT1-HIF-1alpha interaction.
Mesh Terms:
Acetylation, Animals, Cell Hypoxia, Cell Line, Cell Line, Tumor, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Male, Mice, Mice, Nude, Neoplasm Transplantation, Neoplasms, Experimental, Neovascularization, Pathologic, Oxidation-Reduction, Protein Transport, Sirtuin 1, Transplantation, Heterologous, p300-CBP Transcription Factors
Acetylation, Animals, Cell Hypoxia, Cell Line, Cell Line, Tumor, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Male, Mice, Mice, Nude, Neoplasm Transplantation, Neoplasms, Experimental, Neovascularization, Pathologic, Oxidation-Reduction, Protein Transport, Sirtuin 1, Transplantation, Heterologous, p300-CBP Transcription Factors
Mol. Cell
Date: Jun. 25, 2010
PubMed ID: 20620956
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