mAKAP Compartmentalizes Oxygen-Dependent Control of HIF-1
Wei Wong1,
April S. Goehring1,
Michael S. Kapiloff2,
Lorene K. Langeberg3, and
John D. Scott3*
1 Howard Hughes Medical Institute and Vollum Institute, Oregon Health & Science University, 3181 S. W. Sam Jackson Park Road, Portland, OR 97239, USA.
2 Departments of Medicine and Pediatrics, University of Miami, Miller School of Medicine, Miami, FL 33101, USA.
3 Howard Hughes Medical Institute and Department of Pharmacology, University of Washington School of Medicine, 1959 Pacific Avenue NE, HSB K-336B, Box 357370, Seattle, WA 98195, USA.
Abstract:
The activity of the transcription factor hypoxia-inducible factor 1
(HIF-1) is increased in response to reduced intracellular oxygen. Enzymes of the protein ubiquitin machinery that signal the destruction or stabilization of HIF-1 tightly control this transcriptional response. Here, we show that muscle A kinase–anchoring protein (mAKAP) organized ubiquitin E3 ligases that managed the stability of HIF-1 and optimally positioned it close to its site of action inside the nucleus. Functional experiments in cardiomyocytes showed that depletion of mAKAP or disruption of its targeting to the perinuclear region altered the stability of HIF-1 and transcriptional activation of genes associated with hypoxia. Thus, we propose that compartmentalization of oxygen-sensitive signaling components may influence the fidelity and magnitude of the hypoxic response.
* To whom correspondence should be addressed. E-mail: scottjdw{at}u.washington.edu
