• Register
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.


Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.


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


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



Publication Data

November 15, 2007

Associated Grants


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