|
|
Blood, 15 November 2007, Vol. 110, No. 10, pp. 3610-3617.
Prepublished online as a Blood First Edition Paper on August 7, 2007; DOI 10.1182/blood-2007-06-094441.
 Previous Article | Next Article 
Submitted June 7, 2007
Accepted August 6, 2007
Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor
Jens Koditz, Jutta Nesper, Marieke Wottawa, Daniel P Stiehl, Gieri Camenisch, Corinna Franke, Johanna Myllyharju, Roland H Wenger, and Dorthe M Katschinski*
Department of Heart and Circulatory Physiology, Center of Physiology & Pathophysiology, Georg-August University Gottingen, Gottingen, Germany
Cell Physiology Group, Medical Faculty, Martin-Luther University Halle, Halle, Germany
Institute of Physiology, & Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
Collagen Research Unit, Biocenter Oulu, & Dept of Medical Biochemistry & Molecular Biology, University of Oulu, Oulu, Finland
* Corresponding author; email: katschinski{at}physiol.med.uni-goettingen.de.
The activating transcription factor-4 (ATF-4) is translationally induced under anoxic conditions, mediates part of the unfolded protein response following 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 DMOG and hypoxia, or proteasomal inhibition, all induced ATF-4 protein levels. Hypoxic induction of ATF-4 was due to increased protein stability but independent of the ubiquitin ligase pVHL. A novel oxygen-dependent degradation (ODD) domain was identified adjacent to the zipper II domain. Mutations of five prolyl residues within this ODD domain or siRNA-mediated downregulation 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.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
Related Article in Blood Online:
-
A wrinkle in the unfolding of hypoxic response: HIF and ATF4
- Alexander Weidemann and Randall S. Johnson
Blood 2007 110: 3492-3493.
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
J. A. Garcia
Aiming Straight for the Heart: Prolyl Hydroxylases Set the BAR
Sci. Signal.,
November 10, 2009;
2(96):
pe70 - pe70.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A. Gerber, B. Yatsula, C. L. Maier, T. J. Sadler, L. W. Whittaker, and J. S. Pober
Interferon-Gamma Induces Prolyl Hydroxylase (PHD)3 Through a STAT1-Dependent Mechanism in Human Endothelial Cells
Arterioscler Thromb Vasc Biol,
September 1, 2009;
29(9):
1363 - 1369.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Tennant, R. V. Duran, H. Boulahbel, and E. Gottlieb
Metabolic transformation in cancer
Carcinogenesis,
August 1, 2009;
30(8):
1269 - 1280.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. R. Fels, J. Ye, A. T. Segan, S. J. Kridel, M. Spiotto, M. Olson, A. C. Koong, and C. Koumenis
Preferential Cytotoxicity of Bortezomib toward Hypoxic Tumor Cells via Overactivation of Endoplasmic Reticulum Stress Pathways
Cancer Res.,
November 15, 2008;
68(22):
9323 - 9330.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
