Oxygen-dependent hydroxylation by Factor Inhibiting HIF (FIH) regulates the TRPV3 ion channel

Karttunen, Sarah; Duffield, Michael; Scrimgeour, Nathan R.; Squires, Lauren; Lim, Wai Li; Dallas, Mark L.; Scragg, Jason L.; Chicher, Johana; Dave, Keyur A.; Whitelaw, Murray L.; Peers, Chris; Gorman, Jeffrey J.; Gleadle, Jonathan; Rychkov, Grigori Y.; Peet, Daniel J.

doi:10.1242/jcs.158451

Cited by 36 publications

(56 citation statements)

References 35 publications

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“…Oxidant-dependent regulation of TRPV3 was demonstrated by a study showing that severe prolonged hypoxia (24 hrs., 0.1% O 2 ) potentiated 2-aminoethoxydiphenyl borate induced currents in HEK293 cells expressing recombinant TRPV3 channels 109 . This study also showed that the enzyme Factor Inhibiting HIF (FIH), a 2-oxoglutarate-dependent dioxygenase, constitutively hydroxylates asparagine residues within the ankyrin repeat domain of TRPV3, thereby reducing channel activity.…”

Section: S-nytrosylation Of Trpv3 Channelsmentioning

confidence: 93%

Redox regulation of transient receptor potential channels in the endothelium

Pires

Earley

2017

Microcirculation

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Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important mediators of signaling pathways in the endothelium. Specific members of the transient receptor potential (TRP) superfamily of cation channels act as important Ca2+ influx pathways in endothelial cells, and are involved in endothelium-dependent vasodilation, regulation of barrier permeability, and angiogenesis. ROS and RNS can modulate the activity of certain TRP channels mainly by modifying specific cysteine residues or by stimulating the production of second messengers. In this review we highlight the recent literature describing in redox regulation of TRP channel activity in endothelial cells as well as the physiological importance of these pathways and implication for cardiovascular diseases.

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Section: S-nytrosylation Of Trpv3 Channelsmentioning

confidence: 93%

Redox regulation of transient receptor potential channels in the endothelium

Pires

Earley

2017

Microcirculation

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“…TRPV3 responses agonist stimulation can be further potentiated by several factors, including unsaturated fatty acids [101], repetitive heat stimulation [96], or cholesterol [102]. Conversely, factors that suppress TRPV3 activity include oxygen-dependent hydroxylation of TRPV3 by Factor-inhibiting-hypoxia inducible factor [103]. …”

Section: Contributions Of Trp Channels To Skin Biology and Pathophmentioning

confidence: 99%

TRP Channels in Skin Biology and Pathophysiology

Caterina¹,

Pang²

2016

Pharmaceuticals

128

126

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Ion channels of the Transient Receptor Potential (TRP) family mediate the influx of monovalent and/or divalent cations into cells in response to a host of chemical or physical stimuli. In the skin, TRP channels are expressed in many cell types, including keratinocytes, sensory neurons, melanocytes, and immune/inflammatory cells. Within these diverse cell types, TRP channels participate in physiological processes ranging from sensation to skin homeostasis. In addition, there is a growing body of evidence implicating abnormal TRP channel function, as a product of excessive or deficient channel activity, in pathological skin conditions such as chronic pain and itch, dermatitis, vitiligo, alopecia, wound healing, skin carcinogenesis, and skin barrier compromise. These diverse functions, coupled with the fact that many TRP channels possess pharmacologically accessible sites, make this family of proteins appealing therapeutic targets for skin disorders.

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“…Later it was also reported to target non-HIF proteins containing the ankyrin-repeat domain (ARD), such as Notch1-3, IκBα, P105, ASPP2, TRPV3, and OTUB1 (25)(26)(27)(28)(29)(30). As putative ARDs were identified in G9a and GLP on the CDsearch BLAST_NCBI program, we tested the possibility that FIH targets G9a and GLP.…”

Section: Fih Hydroxylates G9a and Glp At The Conserved Asparagine Resmentioning

confidence: 99%

FIH Is an Oxygen Sensor in Ovarian Cancer for G9a/GLP-Driven Epigenetic Regulation of Metastasis-Related Genes

et al. 2018

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The prolyl hydroxlyases PHD1-3 and the asparaginly hydroxlyase FIH are oxygen sensors for HIF-driven transcription of hypoxia-induced genes, but whether these sensors affect oxygendependent epigenetic regulation more broadly is not known. Here we show that FIH exerts an additional role as an oxygen sensor in epigenetic control by the histone lysine methyltransferases G9a and GLP. FIH hydroxylated and inhibited G9a and GLP under normoxia. When the FIH reaction was limited under hypoxia, G9a and GLP were activated and repressed metastasis suppressor genes, thereby triggering cancer cell migration and peritoneal dissemination of ovarian cancer xenografts. In clinical specimens of ovarian cancer, expression of FIH and G9a were reciprocally associated with patient outcomes. We also identified mutations of FIH target motifs in G9a and GLP, which exhibited excessive H3K9 methylation and facilitated cell invasion. This study provides insight into a new function of FIH as an upstream regulator of oxygen-dependent chromatin remodeling. It also implies that the FIH-G9a/GLP pathway could be a potential target for inhibiting hypoxiainduced cancer metastasis.

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Oxygen-dependent hydroxylation by Factor Inhibiting HIF (FIH) regulates the TRPV3 ion channel

Cited by 36 publications

References 35 publications

Redox regulation of transient receptor potential channels in the endothelium

Redox regulation of transient receptor potential channels in the endothelium

TRP Channels in Skin Biology and Pathophysiology

FIH Is an Oxygen Sensor in Ovarian Cancer for G9a/GLP-Driven Epigenetic Regulation of Metastasis-Related Genes

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