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

Bullen, John W.; Tchernyshyov, Irina; Holewinski, Ronald J.; DeVine, Lauren R.; Wu, Fan; Venkatraman, Vidya; Kass, David L.; Cole, Robert N.; Eyk, Jennifer E. Van; Semenza, Gregg L.

doi:10.1126/scisignal.aaf0583

Cited by 81 publications

(61 citation statements)

References 40 publications

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“…It is becoming clear that HIF signaling is regulated not only by low oxygen, but also by several other inflammatory mediators (45)(46)(47). Our data support GC as a further key modulator of HIF signaling to add to this growing list.…”

Section: Discussionsupporting

confidence: 66%

Glucocorticoids promote Von Hippel Lindau degradation and Hif-1α stabilization

Vettori

Greenald

Wilson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Glucocorticoid (GC) and hypoxic transcriptional responses play a central role in tissue homeostasis and regulate the cellular response to stress and inflammation, highlighting the potential for cross-talk between these two signaling pathways. We present results from an unbiased in vivo chemical screen in zebrafish that identifies GCs as activators of hypoxia-inducible factors (HIFs) in the liver. GCs activated consensus hypoxia response element (HRE) reporters in a glucocorticoid receptor (GR)-dependent manner. Importantly, GCs activated HIF transcriptional responses in a zebrafish mutant line harboring a point mutation in the GR DNA-binding domain, suggesting a nontranscriptional route for GR to activate HIF signaling. We noted that GCs increase the transcription of several key regulators of glucose metabolism that contain HREs, suggesting a role for GC/HIF cross-talk in regulating glucose homeostasis. Importantly, we show that GCs stabilize HIF protein in intact human liver tissue and isolated hepatocytes. We find that GCs limit the expression of Von Hippel Lindau protein (pVHL), a negative regulator of HIF, and that treatment with the c-src inhibitor PP2 rescued this effect, suggesting a role for GCs in promoting c-src-mediated proteosomal degradation of pVHL. Our data support a model for GCs to stabilize HIF through activation of c-src and subsequent destabilization of pVHL.hypoxia-inducible factor | glucocorticoid signaling | Von Hippel Lindau | metabolism | liver G lucocorticoids (GCs) are steroid hormones secreted from the adrenal glands that regulate carbohydrate, lipid, and protein metabolism. GCs are widely used as anti-inflammatory agents for treating pathological conditions where hypoxia plays a role in disease progression such as rheumatoid arthritis and chronic obstructive pulmonary disease. GCs and hypoxia pathways have a close interplay in physiology and disease (1-3); however, recent studies report conflicting results on the cross-talk between GC action and hypoxia (4, 5). Hypoxia-inducible factors (HIFs) are oxygen-sensitive transcriptional complexes constituted by α-and β-subunits that activate diverse pathways regulating cellular glucose and lipid metabolism and proliferation (6, 7). Under normoxic conditions, the HIF-1α transcriptional subunit is recognized by prolyl hydroxylases and targeted for degradation via the Von Hippel Lindau (VHL)-mediated ubiquitin proteasome pathway; however, under hypoxic conditions HIF-1α is stabilized and translocates to the nucleus to exert its transcriptional activity. HIFs play a central role in many disease processes and provide a therapeutic target for treating pathological conditions including cancer, ischemia, stroke, inflammation, and chronic anemia (8-11). Screens to identify agents that stabilize HIFs have identified numerous agents, with the majority acting either via iron chelation or as 2-oxyglutarate analogs (12). In vitro HIFreporter screening methods, although extremely valuable, do not provide physiological information and may overlook tissue-s...

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Section: Discussionsupporting

confidence: 66%

Glucocorticoids promote Von Hippel Lindau degradation and Hif-1α stabilization

Vettori

Greenald

Wilson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…This mechanism may be linked to blockade of A2A signaling, with decreased intracellular cAMP levels in turn inhibiting cAMP-dependent protein kinase A (PKA). In line with this hypothesis, recent evidence 58 indicates that PKA is a HIF-1a-interacting protein positively regulating expression of HIF-1a target genes. Likewise, PKAmediated activation of the transcription factor cAMP response element (CRE) binding protein (CREB) induces IL-10 production, 59 providing a direct link between A2A signaling and regulation of gene expression.…”

Section: Discussionmentioning

confidence: 51%

Adenosine signaling mediates hypoxic responses in the chronic lymphocytic leukemia microenvironment

et al. 2016

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Key Points• Hypoxia shapes the CLL lymph node microenvironment by acting through the A2A adenosine receptor.• Inhibiting the A2A adenosine receptor counteracts the effects of hypoxia on CLL cells, macrophages, and T lymphocytes. adenosine receptor counteracts these effects on all cell populations, making leukemic cells more susceptible to pharmacological agents while restoring immune competence and T-cell proliferation. Together, these results indicate that adenosine signaling through the A2A receptor mediates part of the effects of hypoxia. They also suggest that therapeutic strategies to inhibit the adenosinergic axis may be useful adjuncts to chemotherapy or tyrosine kinase inhibitors in the treatment of CLL patients.

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“…As O 2 destabilizes both isoforms by activating prolyl hydroxylases, HIF-2α accumulation in hyperoxia seems paradoxical, but similar patterns were observed in prostate tumors [42], brain tissue [5], hepatocytes and liver hemopoietic cells in newborn rats [43], as well as in embryonic myocardium [44]. The molecular mechanisms underlying HIF-1α activation independently of hydroxylation are being elucidated [45]. Remarkably, the redox imbalance in the sympathetic nervous system is caused by the disruption of the balance between HIF-1α-dependent pro-oxidant and HIF-2α-dependent antioxidant enzymes [46].…”

Section: Discussionmentioning

confidence: 91%

Brain adaptation to hypoxia and hyperoxia in mice

et al. 2017

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AimsHyperoxic breathing might lead to redox imbalance and signaling changes that affect cerebral function. Paradoxically, hypoxic breathing is also believed to cause oxidative stress. Our aim is to dissect the cerebral tissue responses to altered O2 fractions in breathed air by assessing the redox imbalance and the recruitment of the hypoxia signaling pathways.ResultsMice were exposed to mild hypoxia (10%O2), normoxia (21%O2) or mild hyperoxia (30%O2) for 28 days, sacrificed and brain tissue excised and analyzed. Although one might expect linear responses to %O2, only few of the examined variables exhibited this pattern, including neuroprotective phospho- protein kinase B and the erythropoietin receptor. The major reactive oxygen species (ROS) source in brain, NADPH oxidase subunit 4 increased in hypoxia but not in hyperoxia, whereas neither affected nuclear factor (erythroid-derived 2)-like 2, a transcription factor that regulates the expression of antioxidant proteins. As a result of the delicate equilibrium between ROS generation and antioxidant defense, neuron apoptosis and cerebral tissue hydroperoxides increased in both 10%O2 and 30%O2, as compared with 21%O2. Remarkably, the expression level of hypoxia-inducible factor (HIF)−2α (but not HIF-1α) was higher in both 10%O2 and 30%O2 with respect to 21%O2InnovationComparing the in vivo effects driven by mild hypoxia with those driven by mild hyperoxia helps addressing whether clinically relevant situations of O2 excess and scarcity are toxic for the organism.ConclusionProlonged mild hyperoxia leads to persistent cerebral damage, comparable to that inferred by prolonged mild hypoxia. The underlying mechanism appears related to a model whereby the imbalance between ROS generation and anti-ROS defense is similar, but occurs at higher levels in hypoxia than in hyperoxia.

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

Cited by 81 publications

References 40 publications

Glucocorticoids promote Von Hippel Lindau degradation and Hif-1α stabilization

Glucocorticoids promote Von Hippel Lindau degradation and Hif-1α stabilization

Adenosine signaling mediates hypoxic responses in the chronic lymphocytic leukemia microenvironment

Brain adaptation to hypoxia and hyperoxia in mice

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