Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-2733
Köditz, J; Nesper, J; Wottawa, M; Stiehl, D P; Camenisch, G; Franke, C; Myllyharju, J; Wenger, R H; Katschinski, D M (2007). Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor. Blood, 110(10):3610-3617.
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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.
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|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
|DDC:||570 Life sciences; biology|
|Deposited On:||22 Aug 2008 11:53|
|Last Modified:||28 Nov 2013 01:28|
|Publisher:||American Society of Hematology|
|Additional Information:||This research was originally published in Blood, 2007; 110(10):3610-17. Copyright by the American Society of Hematology|
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