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Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor.

Blood | Nov 15, 2007

The activating transcription factor-4 (ATF-4) is translationally induced under anoxic conditions, mediates part of the unfolded protein response following endoplasmic reticulum (ER) stress, and is a critical regulator of cell fate. Here, we identified the zipper II domain of ATF-4 to interact with the oxygen sensor prolyl-4-hydroxylase domain 3 (PHD3). The PHD inhibitors dimethyloxalylglycine (DMOG) and hypoxia, or proteasomal inhibition, all induced ATF-4 protein levels. Hypoxic induction of ATF-4 was due to increased protein stability, but was independent of the ubiquitin ligase von Hippel-Lindau protein (pVHL). A novel oxygen-dependent degradation (ODD) domain was identified adjacent to the zipper II domain. Mutations of 5 prolyl residues within this ODD domain or siRNA-mediated down-regulation of PHD3, but not of PHD2, was sufficient to stabilize ATF-4 under normoxic conditions. These data demonstrate that PHD-dependent oxygen-sensing recruits both the hypoxia-inducible factor (HIF) and ATF-4 systems, and hence not only confers adaptive responses but also cell fate decisions.

Pubmed ID: 17684156 RIS Download

Mesh terms: Activating Transcription Factor 4 | Amino Acid Sequence | Cell Hypoxia | Dioxygenases | HeLa Cells | Humans | Hypoxia-Inducible Factor 1, alpha Subunit | Hypoxia-Inducible Factor-Proline Dioxygenases | Molecular Sequence Data | Oxygen | Protein Binding | Protein Processing, Post-Translational | Protein Structure, Tertiary | Sequence Homology, Amino Acid

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