Proteomics

Dataset Information

71

Protein kinase A-dependent phosphorylation stimulates the transcriptional activity of hypoxia-inducible factor 1, part 2


ABSTRACT: Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes encoding proteins that enable cells to adapt to reduced O2 availability. HIF-1 controls physiological processes that are dysregulated in cancer and heart disease, including angiogenesis, energy metabolism, and immunity. These disease processes are also characterized by increased activation of adenosine and β-adrenergic receptors, which triggers the synthesis of cyclic adenosine monophosphate (cAMP), the allosteric regulator of cAMP-dependent protein kinase A (PKA). We performed a proteomic screen in cardiomyocytes and identified PKA as a HIF-1α-interacting protein. PKA interacted with HIF-1α and phosphorylated Thr63 and Ser692 in vitro, coimmunoprecipitated with HIF-1α from cell lysates, and enhanced HIF transcriptional activity and target gene expression in human HeLa cells and rat cardiomyocytes. PKA inhibited the proteasomal degradation of HIF-1α in an O2-independent manner that required phosphorylation of Thr63 and Ser692 and was not affected by mutation of Pro402 and Pro564. PKA also stimulated the binding of the coactivator p300 to HIF- 1α to enhance its transcriptional activity and this effect was lost upon mutation of Asn803. These data establish a potential link between stimuli that increase cAMP concentrations and HIF-1α-dependent changes in gene expression, which contribute to the pathophysiology of cancer and heart disease.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Rattus norvegicus  

TISSUE(S): Tissue Not Applicable To Dataset

DISEASE(S): Hypertrophic Cardiomyopathy

SUBMITTER: Vidya Venkatraman  

LAB HEAD: Gregg L. Semenza

PROVIDER: PXD003795 | Pride | 2016-06-07

REPOSITORIES: Pride

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Publications

Protein kinase A-dependent phosphorylation stimulates the transcriptional activity of hypoxia-inducible factor 1.

Bullen John W JW   Tchernyshyov Irina I   Holewinski Ronald J RJ   DeVine Lauren L   Wu Fan F   Venkatraman Vidya V   Kass David L DL   Cole Robert N RN   Van Eyk Jennifer J   Semenza Gregg L GL  

Science signaling 20160531 430


Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes encoding proteins that enable cells to adapt to reduced O2 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-  ...[more]

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