In:
Science Signaling, American Association for the Advancement of Science (AAAS), Vol. 9, No. 430 ( 2016-05-31)
Abstract:
Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes encoding proteins that enable cells to adapt to reduced O 2 availability. Proteins encoded by HIF-1 target genes play a central role in mediating physiological processes that are dysregulated in cancer and heart disease. These diseases are also characterized by increased production of cyclic adenosine monophosphate (cAMP), the allosteric activator of cAMP-dependent protein kinase A (PKA). Using glutathione S -transferase pull-down, coimmunoprecipitation, and mass spectrometry analyses, we demonstrated that PKA interacts with HIF-1α in HeLa cervical carcinoma cells and rat cardiomyocytes. PKA phosphorylated Thr 63 and Ser 692 on HIF-1α in vitro and enhanced HIF transcriptional activity and target gene expression in HeLa cells and rat cardiomyocytes. PKA inhibited the proteasomal degradation of HIF-1α in an O 2 -independent manner that required the phosphorylation of Thr 63 and Ser 692 and was not affected by prolyl hydroxylation. PKA also stimulated the binding of the coactivator p300 to HIF-1α to enhance its transcriptional activity and counteracted the inhibitory effect of asparaginyl hydroxylation on the association of p300 with HIF-1α. Furthermore, increased cAMP concentrations enhanced the expression of HIF target genes encoding CD39 and CD73, which are enzymes that convert extracellular adenosine 5′-triphosphate to adenosine, a molecule that enhances tumor immunosuppression and reduces heart rate and contractility. These data link stimuli that promote cAMP signaling, HIF-1α–dependent changes in gene expression, and increased adenosine, all of which contribute to the pathophysiology of cancer and heart disease.
Type of Medium:
Online Resource
ISSN:
1945-0877
,
1937-9145
DOI:
10.1126/scisignal.aaf0583
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2016
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