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

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

Authors

  • K√∂ditz J
  • Nesper J
  • Wottawa M
  • Stiehl DP
  • Camenisch G
  • Franke C
  • Myllyharju J
  • Wenger RH
  • Katschinski DM

Journal

Blood

Publication Data

November 15, 2007

Associated Grants

None

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