The Acetylase/Deacetylase Couple CREB-binding Protein/Sirtuin 1 Controls Hypoxia-inducible Factor 2 Signaling

Chen, Rui; Xu, Min; Hogg, Richard T.; Li, Jiwen; Little, Bertis B.; Gerard, Robert D.; Garcia, Joseph A.

doi:10.1074/jbc.m111.244780

Cited by 75 publications

(100 citation statements)

References 41 publications

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“…They also showed that HIF-2α acetylation under hypoxia is reversed, i.e., deacetylated, by Sirtuin 1 (Sirt1) and that the deacetylation process augments rather than dampens HIF-2 signaling [53]. Although the precise mechanism is yet to be determined, this cyclical acetylation by CBP and deacetylation by Sirt1 appears to be necessary for efficient HIF-2 signaling during hypoxia rather than being only an on/off switch [52,54].…”

Section: Noncanonical Hif Regulation In the Kidneymentioning

confidence: 99%

“…Garcia and colleagues [51,52] demonstrated that acetyl CoA synthetase 2-dependent HIF-2α acetylation at specific lysine residues by CBP and formation of the CBP-HIF-2α complex are essential for the efficient induction of EPO in the kidney and liver under hypoxic conditions. They also showed that HIF-2α acetylation under hypoxia is reversed, i.e., deacetylated, by Sirtuin 1 (Sirt1) and that the deacetylation process augments rather than dampens HIF-2 signaling [53].…”

Section: Noncanonical Hif Regulation In the Kidneymentioning

confidence: 99%

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Hypoxia and hypoxia-inducible factors in chronic kidney disease

Tanaka

Nangaku

2016

Ren Replace Ther

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It is generally accepted that renal hypoxia plays an important role in the progression of chronic kidney disease (CKD). This review focuses on renal hypoxia and hypoxia-inducible factor (HIF), a master regulator of cellular adaptation to hypoxia, during CKD progression. The kidney, which is physiologically hypoxic, is exposed to increased levels of hypoxia in CKD; insufficient oxygenation in the tubulointerstitium triggers injury and accelerates the deterioration of renal function, culminating in end-stage kidney disease (ESKD). HIF accumulates during specific stages of pathological progression; however, adaptation to hypoxia usually fails. In such cases, decreased vascular endothelial growth factor expression and upregulated antiangiogenic factors result in sustained capillary rarefaction. In addition, oxygen consumption in tubules is primarily increased by enhanced oxidative stress, and the transcriptional activity of HIF becomes suboptimal, which is partly mediated by methylglyoxal in diabetic kidney disease and by indoxyl sulfate, a representative uremic toxin, in advanced CKD. Oxygen-dependent canonical regulators of HIF involve prolyl hydroxylase domain-containing protein (PHD) and factor inhibiting HIF-1 (FIH-1), whereas recent studies have revealed noncanonical and oxygen-independent HIF regulation in the kidney. As a consequence, HIF accumulation usually fails to protect the kidney against hypoxia, which is likely to accelerate progression to ESKD, via several maladaptation mechanisms. The precise roles of HIF and its regulation in CKD warrant further investigation in light of promising data demonstrating that HIF stabilization by PHD inhibitors may be a new therapeutic approach for CKD.

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Section: Noncanonical Hif Regulation In the Kidneymentioning

confidence: 99%

Section: Noncanonical Hif Regulation In the Kidneymentioning

confidence: 99%

Hypoxia and hypoxia-inducible factors in chronic kidney disease

Tanaka

Nangaku

2016

Ren Replace Ther

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“…Whereas HIF-1α regulation by major signal transduction pathways has been extensively studied (Kietzmann et al, 2016) our knowledge about how HIF-2α is regulated remains quite limited. It has been reported that HIF-2α is acetylated at several lysine residues by CPB (Chen et al, 2012) and de-acetylated by SIRT1 (Dioum et al, 2009;Lim et al, 2010) but there is contradictory evidence concerning the role of these modifications. Moreover, HIF-2α is phosphorylated at Thr324 by PKD1 and, as a result, its interaction with the SP1 transcription factor is inhibited, thus promoting NBS1 (also known as NBN) expression .…”

Section: Introductionmentioning

confidence: 99%

HIF-2α phosphorylation by CK1δ promotes erythropoietin secretion in liver cancer cells under hypoxia

Pangou

Befani

Mylonis

et al. 2016

Journal of Cell Science

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Hypoxia inducible factor 2 (HIF-2) is a transcriptional activator implicated in the cellular response to hypoxia. Regulation of its inducible subunit, HIF-2α (also known as EPAS1), involves posttranslational modifications. Here, we demonstrate that casein kinase 1δ (CK1δ; also known as CSNK1D) phosphorylates HIF-2α at Ser383 and Thr528 in vitro. We found that disruption of these phosphorylation sites, and silencing or chemical inhibition of CK1δ, reduced the expression of HIF-2 target genes and the secretion of erythropoietin (EPO) in two hepatic cancer cell lines, Huh7 and HepG2, without affecting the levels of HIF-2α protein expression. Furthermore, when CK1δ-dependent phosphorylation of HIF-2α was inhibited, we observed substantial cytoplasmic mislocalization of HIF-2α, which was reversed upon the addition of the nuclear protein export inhibitor leptomycin B. Taken together, these data suggest that CK1δ enhances EPO secretion from liver cancer cells under hypoxia by modifying HIF-2α and promoting its nuclear accumulation. This modification represents a new mechanism of HIF-2 regulation that might allow HIF isoforms to undertake differing functions.

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“…As the founding member of the sirtuin family, the effects of Sirt1 have been best characterized. Sirt1 was identified as a HIF-2␣ deacetylase that augments HIF-2 (but not HIF-1) activity (24,25). A subsequent study suggested that Sirt1 may repress HIF-1 transactivation ability (26), whereas a third study reported that Sirt1 increased HIF-1␣ protein levels (27).…”

mentioning

confidence: 98%