Regulation of Hypoxia-Inducible Factor 2
Signaling by the Stress-Responsive Deacetylase Sirtuin 1
Elhadji M. Dioum,1,2,*
Rui Chen,1,2,*
Matthew S. Alexander,2
Quiyang Zhang,2
Richard T. Hogg,2
Robert D. Gerard,2,3
Joseph A. Garcia1,2,
To survive in hostile environments, organisms activate stress-responsive
transcriptional regulators that coordinately increase production
of protective factors. Hypoxia changes cellular metabolism and
thus activates redox-sensitive as well as oxygen-dependent signal
transducers. We demonstrate that Sirtuin 1 (Sirt1), a redox-sensing
deacetylase, selectively stimulates activity of the transcription
factor hypoxia-inducible factor 2 alpha (HIF-2
) during hypoxia.
The effect of Sirt1 on HIF-2
required direct interaction of
the proteins and intact deacetylase activity of Sirt1. Select
lysine residues in HIF-2
that are acetylated during hypoxia
confer repression of Sirt1 augmentation by small-molecule inhibitors.
In cultured cells and mice, decreasing or increasing Sirt1 activity
or levels affected expression of the HIF-2
target gene erythropoietin
accordingly. Thus, Sirt1 promotes HIF-2 signaling during hypoxia
and likely other environmental stresses.
2 University of Texas Southwestern Medical Center at Dallas, Department of Internal Medicine, 5323 Harry Hines Boulevard, Dallas, TX 75390–8573, USA.
3 University of Texas Southwestern Medical Center at Dallas, Department of Molecular Biology, 5323 Harry Hines Boulevard, Dallas, TX 75390–8573, USA.
* These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: joseph.garcia{at}utsouthwestern.edu
