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Article ; Online: Intestinal hypoxia and hypoxia-induced signalling as therapeutic targets for IBD.

Van Welden, Sophie / Selfridge, Andrew C / Hindryckx, Pieter

Nature reviews. Gastroenterology & hepatology

2017 Volume 14, Issue 10, Page(s) 596–611

Abstract: Tissue hypoxia occurs when local oxygen demand exceeds oxygen supply. In chronic inflammatory conditions such as IBD, the increased oxygen demand by resident and gut-infiltrating immune cells coupled with vascular dysfunction brings about a marked ... ...

Abstract	Tissue hypoxia occurs when local oxygen demand exceeds oxygen supply. In chronic inflammatory conditions such as IBD, the increased oxygen demand by resident and gut-infiltrating immune cells coupled with vascular dysfunction brings about a marked reduction in mucosal oxygen concentrations. To counter the hypoxic challenge and ensure their survival, mucosal cells induce adaptive responses, including the activation of hypoxia-inducible factors (HIFs) and modulation of nuclear factor-κB (NF-κB). Both pathways are tightly regulated by oxygen-sensitive prolyl hydroxylases (PHDs), which therefore represent promising therapeutic targets for IBD. In this Review, we discuss the involvement of mucosal hypoxia and hypoxia-induced signalling in the pathogenesis of IBD and elaborate in detail on the role of HIFs, NF-κB and PHDs in different cell types during intestinal inflammation. We also provide an update on the development of PHD inhibitors and discuss their therapeutic potential in IBD.
MeSH term(s)	Humans ; Hypoxia/metabolism ; Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism ; Inflammatory Bowel Diseases/drug therapy ; Inflammatory Bowel Diseases/immunology ; Inflammatory Bowel Diseases/metabolism ; Intestinal Mucosa/cytology ; Intestinal Mucosa/metabolism ; NF-kappa B/metabolism ; Signal Transduction
Chemical Substances	NF-kappa B ; Hypoxia-Inducible Factor-Proline Dioxygenases (EC 1.14.11.29)
Language	English
Publishing date	2017-10
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2493722-8
ISSN	1759-5053 ; 1759-5045
ISSN (online)	1759-5053
ISSN	1759-5045
DOI	10.1038/nrgastro.2017.101
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Article ; Online: Carbon dioxide-dependent regulation of NF-κB family members RelB and p100 gives molecular insight into CO

Keogh, Ciara E / Scholz, Carsten C / Rodriguez, Javier / Selfridge, Andrew C / von Kriegsheim, Alexander / Cummins, Eoin P

The Journal of biological chemistry

2017 Volume 292, Issue 27, Page(s) 11561–11571

Abstract: ... ...

Abstract	CO
MeSH term(s)	A549 Cells ; Animals ; Carbon Dioxide/immunology ; Humans ; Hypercapnia/genetics ; Hypercapnia/immunology ; Hypercapnia/pathology ; Mice ; NF-kappa B p52 Subunit/genetics ; NF-kappa B p52 Subunit/immunology ; Protein Domains ; Signal Transduction/genetics ; Signal Transduction/immunology ; Transcription Factor RelB/genetics ; Transcription Factor RelB/immunology ; Transcription, Genetic/genetics ; Transcription, Genetic/immunology
Chemical Substances	NF-kappa B p52 Subunit ; NFKB2 protein, human ; Nfkb2 protein, mouse ; RELB protein, human ; Relb protein, mouse ; Carbon Dioxide (142M471B3J) ; Transcription Factor RelB (147337-75-5)
Language	English
Publishing date	2017-05-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M116.755090
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Article ; Online: DNA-Based Photoacoustic Nanosensor for Interferon Gamma Detection.

Morales, Jennifer / Pawle, Robert H / Akkilic, Namik / Luo, Yi / Xavierselvan, Marvin / Albokhari, Rayan / Calderon, Isen Andrew C / Selfridge, Scott / Minns, Richard / Takiff, Larry / Mallidi, Srivalleesha / Clark, Heather A

ACS sensors

2019 Volume 4, Issue 5, Page(s) 1313–1322

Abstract: ... with an affinity in the nanomolar range, K ...

Abstract	Tracking protein levels in the body is vital in both research and medicine, where understanding their physiological roles provides insight into their regulation in homeostasis and diseases. In medicine, protein levels are actively sampled since they continuously fluctuate, reflecting the status of biological systems and provide insight into patient health. One such protein is interferon gamma, a clinically relevant protein with immunoregulatory functions that play critical roles against infection. New tools for continuously monitoring protein levels in vivo are invaluable in monitoring real-time conditions of patients to allow better care. Here, we developed a DNA-based nanosensor for the photoacoustic detection of interferon gamma. This work demonstrates how we transformed a simple DNA motif, receptors, and a novel phthalocyanine dye into a proof-of-concept photoacoustic nanosensor for protein detection. Surface plasmon resonance kinetic analysis demonstrated that the nanosensor is responsive and reversible to interferon gamma with an affinity in the nanomolar range, K
MeSH term(s)	Biosensing Techniques/methods ; DNA/chemistry ; DNA/metabolism ; Interferon-gamma/analysis ; Limit of Detection ; Models, Molecular ; Nanotechnology/methods ; Nucleic Acid Conformation ; Photoacoustic Techniques
Chemical Substances	Interferon-gamma (82115-62-6) ; DNA (9007-49-2)
Language	English
Publishing date	2019-04-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2379-3694
ISSN (online)	2379-3694
DOI	10.1021/acssensors.9b00209
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Article ; Online: Stereochemistry and innate immune recognition: (+)-norbinaltorphimine targets myeloid differentiation protein 2 and inhibits toll-like receptor 4 signaling.

Zhang, Xiaozheng / Peng, Yinghua / Grace, Peter M / Metcalf, Matthew D / Kwilasz, Andrew J / Wang, Yibo / Zhang, Tianshu / Wu, Siru / Selfridge, Brandon R / Portoghese, Philip S / Rice, Kenner C / Watkins, Linda R / Hutchinson, Mark R / Wang, Xiaohui

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2019 Volume 33, Issue 8, Page(s) 9577–9587

Abstract: Deregulation of innate immune TLR4 signaling contributes to various diseases including neuropathic pain and drug addiction. Naltrexone is one of the rare TLR4 antagonists with good blood-brain barrier permeability and showing no stereoselectivity for ... ...

Abstract	Deregulation of innate immune TLR4 signaling contributes to various diseases including neuropathic pain and drug addiction. Naltrexone is one of the rare TLR4 antagonists with good blood-brain barrier permeability and showing no stereoselectivity for TLR4. By linking 2 naltrexone units through a rigid pyrrole spacer, the bivalent ligand norbinaltorphimine was formed. Interestingly, (+)-norbinaltorphimine [(+)-1] showed ∼25 times better TLR4 antagonist activity than naltrexone in microglial BV-2 cell line, whereas (-)-norbinaltorphimine [(-)-1] lost TLR4 activity. The enantioselectivity of norbinaltorphimine was further confirmed in primary microglia, astrocytes, and macrophages. The activities of meso isomer of norbinaltorphimine and the molecular dynamic simulation results demonstrate that the stereochemistry of (+)-1 is derived from the (+)-naltrexone pharmacophore. Moreover, (+)-1 significantly increased and prolonged morphine analgesia
MeSH term(s)	Animals ; Astrocytes/drug effects ; Astrocytes/metabolism ; Cell Differentiation/drug effects ; Cell Line ; Cells, Cultured ; Interleukin-1beta/metabolism ; Lymphocyte Antigen 96/metabolism ; Male ; Mice ; Microglia/drug effects ; Microglia/metabolism ; Naltrexone/analogs & derivatives ; Naltrexone/chemistry ; Naltrexone/pharmacology ; Protein Structure, Secondary ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; Stereoisomerism ; Structure-Activity Relationship ; Toll-Like Receptor 4/antagonists & inhibitors ; Toll-Like Receptor 4/metabolism ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	Interleukin-1beta ; Ly96 protein, mouse ; Lymphocyte Antigen 96 ; Toll-Like Receptor 4 ; Tumor Necrosis Factor-alpha ; norbinaltorphimine (36OOQ86QM1) ; Naltrexone (5S6W795CQM)
Language	English
Publishing date	2019-06-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.201900173RRR
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Zs.A 2266: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Carbon dioxide-sensing in organisms and its implications for human disease.

Cummins, Eoin P / Selfridge, Andrew C / Sporn, Peter H / Sznajder, Jacob I / Taylor, Cormac T

Cellular and molecular life sciences : CMLS

2013 Volume 71, Issue 5, Page(s) 831–845

Abstract: The capacity of organisms to sense changes in the levels of internal and external gases and to respond accordingly is central to a range of physiologic and pathophysiologic processes. Carbon dioxide, a primary product of oxidative metabolism is one such ... ...

Abstract	The capacity of organisms to sense changes in the levels of internal and external gases and to respond accordingly is central to a range of physiologic and pathophysiologic processes. Carbon dioxide, a primary product of oxidative metabolism is one such gas that can be sensed by both prokaryotic and eukaryotic cells and in response to altered levels, elicit the activation of multiple adaptive pathways. The outcomes of activating CO2-sensitive pathways in various species include increased virulence of fungal and bacterial pathogens, prey-seeking behavior in insects as well as taste perception, lung function, and the control of immunity in mammals. In this review, we discuss what is known about the mechanisms underpinning CO2 sensing across a range of species and consider the implications of this for physiology, disease progression, and the possibility of developing new therapeutics for inflammatory and infectious disease.
MeSH term(s)	Adaptation, Biological/physiology ; Adenylyl Cyclases/metabolism ; Animals ; Aquaporins/metabolism ; Carbon Dioxide/metabolism ; Carbonic Anhydrases/metabolism ; Chemoreceptor Cells/physiology ; Connexins/metabolism ; Humans ; Infections/metabolism ; Inflammation/metabolism ; Microbial Viability ; Models, Biological ; Respiration ; Signal Transduction/physiology ; Species Specificity
Chemical Substances	Aquaporins ; Connexins ; Carbon Dioxide (142M471B3J) ; Carbonic Anhydrases (EC 4.2.1.1) ; Adenylyl Cyclases (EC 4.6.1.1)
Language	English
Publishing date	2013-09-18
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-013-1470-6
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Article ; Online: Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia.

Selfridge, Andrew C / Cavadas, Miguel A S / Scholz, Carsten C / Campbell, Eric L / Welch, Lynn C / Lecuona, Emilia / Colgan, Sean P / Barrett, Kim E / Sporn, Peter H S / Sznajder, Jacob I / Cummins, Eoin P / Taylor, Cormac T

The Journal of biological chemistry

2016 Volume 291, Issue 22, Page(s) 11800–11808

Abstract: Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of ... ...

Abstract	Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states, including acute and chronic respiratory diseases. The hypoxia-inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia; however, little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-α protein stability and HIF target gene expression both in mice and cultured cells in a manner that was at least in part independent of the canonical O2-dependent HIF degradation pathway. The suppressive effects of hypercapnia on HIF-α protein stability could be mimicked by reducing intracellular pH at a constant level of partial pressure of CO2 Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase that blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-α protein. Based on these results, we hypothesize that hypercapnia counter-regulates activation of the HIF pathway by reducing intracellular pH and promoting lysosomal degradation of HIF-α subunits. Therefore, hypercapnia may play a key role in the pathophysiology of diseases where HIF is implicated.
MeSH term(s)	Animals ; Blotting, Western ; Carbon Dioxide/blood ; Cells, Cultured ; Female ; HCT116 Cells ; HeLa Cells ; Humans ; Hydrogen-Ion Concentration ; Hypercapnia/physiopathology ; Hypoxia/physiopathology ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Oxygen/metabolism ; Real-Time Polymerase Chain Reaction
Chemical Substances	Hypoxia-Inducible Factor 1, alpha Subunit ; Carbon Dioxide (142M471B3J) ; Oxygen (S88TT14065)
Language	English
Publishing date	2016-04-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M116.713941
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Article ; Online: REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia.

Cavadas, Miguel A S / Mesnieres, Marion / Crifo, Bianca / Manresa, Mario C / Selfridge, Andrew C / Scholz, Carsten C / Cummins, Eoin P / Cheong, Alex / Taylor, Cormac T

Scientific reports

2015 Volume 5, Page(s) 17851

Abstract: The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1α expression in hypoxia must be carefully ... ...

Abstract	The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1α expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1α mRNA is suppressed in prolonged hypoxia, suggesting that the control of HIF1A gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1α protein response and the suppression of HIF-1α mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1α promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1α mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1α- (but not HIF-2α-) dependent manner. Finally, REST promotes the resolution of HIF-1α protein expression in prolonged hypoxia. In conclusion, we hypothesize that REST represses transcription of HIF-1α in prolonged hypoxia, thus contributing to the resolution of the HIF-1α response.
MeSH term(s)	Base Sequence ; Binding Sites ; Computational Biology ; Gene Expression Regulation ; Glucose/metabolism ; Glycolysis ; Humans ; Hypoxia/genetics ; Hypoxia/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/chemistry ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Lactic Acid/biosynthesis ; Molecular Sequence Data ; Oxygen/metabolism ; Promoter Regions, Genetic ; Protein Binding ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Repressor Proteins/metabolism ; Sequence Alignment
Chemical Substances	Hypoxia-Inducible Factor 1, alpha Subunit ; RE1-silencing transcription factor ; RNA, Messenger ; Repressor Proteins ; Lactic Acid (33X04XA5AT) ; Glucose (IY9XDZ35W2) ; Oxygen (S88TT14065)
Language	English
Publishing date	2015-12-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep17851
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Article ; Online: REST is a hypoxia-responsive transcriptional repressor.

Cavadas, Miguel A S / Mesnieres, Marion / Crifo, Bianca / Manresa, Mario C / Selfridge, Andrew C / Keogh, Ciara E / Fabian, Zsolt / Scholz, Carsten C / Nolan, Karen A / Rocha, Liliane M A / Tambuwala, Murtaza M / Brown, Stuart / Wdowicz, Anita / Corbett, Danielle / Murphy, Keith J / Godson, Catherine / Cummins, Eoin P / Taylor, Cormac T / Cheong, Alex

Scientific reports

2016 Volume 6, Page(s) 31355

Abstract: Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. Discrete cohorts of genes can be either up- or down-regulated in response to hypoxia. While the Hypoxia-Inducible Factor (HIF) is the ... ...

Abstract	Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. Discrete cohorts of genes can be either up- or down-regulated in response to hypoxia. While the Hypoxia-Inducible Factor (HIF) is the primary driver of hypoxia-induced adaptive gene expression, less is known about the signalling mechanisms regulating hypoxia-dependent gene repression. Using RNA-seq, we demonstrate that equivalent numbers of genes are induced and repressed in human embryonic kidney (HEK293) cells. We demonstrate that nuclear localization of the Repressor Element 1-Silencing Transcription factor (REST) is induced in hypoxia and that REST is responsible for regulating approximately 20% of the hypoxia-repressed genes. Using chromatin immunoprecipitation assays we demonstrate that REST-dependent gene repression is at least in part mediated by direct binding to the promoters of target genes. Based on these data, we propose that REST is a key mediator of gene repression in hypoxia.
Language	English
Publishing date	2016-08-17
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep31355
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Article ; Online: A dominant role for the methyl-CpG-binding protein Mbd2 in controlling Th2 induction by dendritic cells.

Cook, Peter C / Owen, Heather / Deaton, Aimée M / Borger, Jessica G / Brown, Sheila L / Clouaire, Thomas / Jones, Gareth-Rhys / Jones, Lucy H / Lundie, Rachel J / Marley, Angela K / Morrison, Vicky L / Phythian-Adams, Alexander T / Wachter, Elisabeth / Webb, Lauren M / Sutherland, Tara E / Thomas, Graham D / Grainger, John R / Selfridge, Jim / McKenzie, Andrew N J /

Allen, Judith E / Fagerholm, Susanna C / Maizels, Rick M / Ivens, Alasdair C / Bird, Adrian / MacDonald, Andrew S

Nature communications

2015 Volume 6, Page(s) 6920

Abstract: Dendritic cells (DCs) direct CD4(+) T-cell differentiation into diverse helper (Th) subsets that are required for protection against varied infections. However, the mechanisms used by DCs to promote Th2 responses, which are important both for immunity to ...

Abstract	Dendritic cells (DCs) direct CD4(+) T-cell differentiation into diverse helper (Th) subsets that are required for protection against varied infections. However, the mechanisms used by DCs to promote Th2 responses, which are important both for immunity to helminth infection and in allergic disease, are currently poorly understood. We demonstrate a key role for the protein methyl-CpG-binding domain-2 (Mbd2), which links DNA methylation to repressive chromatin structure, in regulating expression of a range of genes that are associated with optimal DC activation and function. In the absence of Mbd2, DCs display reduced phenotypic activation and a markedly impaired capacity to initiate Th2 immunity against helminths or allergens. These data identify an epigenetic mechanism that is central to the activation of CD4(+) T-cell responses by DCs, particularly in Th2 settings, and reveal methyl-CpG-binding proteins and the genes under their control as possible therapeutic targets for type-2 inflammation.
MeSH term(s)	Allergens ; Animals ; CD4-Positive T-Lymphocytes/immunology ; Cell Polarity ; Chromatin Immunoprecipitation ; DNA Methylation ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/immunology ; Dendritic Cells/immunology ; Enzyme-Linked Immunosorbent Assay ; Epigenesis, Genetic ; Flow Cytometry ; Gene Expression Regulation/genetics ; Hypersensitivity/immunology ; Lymphocyte Activation/immunology ; Mice ; Mice, Knockout ; Pyroglyphidae/immunology ; RNA, Messenger/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Schistosoma mansoni/immunology ; Schistosomiasis mansoni/immunology ; Th2 Cells/immunology
Chemical Substances	Allergens ; DNA-Binding Proteins ; Mbd2 protein, mouse ; RNA, Messenger
Language	English
Publishing date	2015-04-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/ncomms7920
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Article ; Online: Identification of retinol binding protein 1 promoter hypermethylation in isocitrate dehydrogenase 1 and 2 mutant gliomas.

Chou, Arthur P / Chowdhury, Reshmi / Li, Sichen / Chen, Weidong / Kim, Andrew J / Piccioni, David E / Selfridge, Julia M / Mody, Reema R / Chang, Stephen / Lalezari, Shadi / Lin, Jeffrey / Sanchez, Desiree E / Wilson, Ryan W / Garrett, Matthew C / Harry, Bret / Mottahedeh, Jack / Nghiemphu, Phioanh L / Kornblum, Harley I / Mischel, Paul S /

Prins, Robert M / Yong, William H / Cloughesy, Timothy / Nelson, Stanley F / Liau, Linda M / Lai, Albert

Journal of the National Cancer Institute

2012 Volume 104, Issue 19, Page(s) 1458–1469

Abstract: Background: Mutations in isocitrate dehydrogenase 1 (IDH1) and associated CpG island hypermethylation represent early events in the development of low-grade gliomas and secondary glioblastomas. To identify candidate tumor suppressor genes whose promoter ...

Abstract	Background: Mutations in isocitrate dehydrogenase 1 (IDH1) and associated CpG island hypermethylation represent early events in the development of low-grade gliomas and secondary glioblastomas. To identify candidate tumor suppressor genes whose promoter methylation may contribute to gliomagenesis, we compared methylation profiles of IDH1 mutant (MUT) and IDH1 wild-type (WT) tumors using massively parallel reduced representation bisulfite sequencing. Methods: Reduced representation bisulfite sequencing was performed on ten pathologically matched WT and MUT glioma samples and compared with data from a methylation-sensitive restriction enzyme technique and data from The Cancer Genome Atlas (TCGA). Methylation in the gene retinol-binding protein 1 (RBP1) was identified in IDH1 mutant tumors and further analyzed with primer-based bisulfite sequencing. Correlation between IDH1/IDH2 mutation status and RBP1 methylation was evaluated with Spearman correlation. Survival data were collected retrospectively and analyzed with Kaplan-Meier and Cox proportional hazards analysis. All statistical tests were two-sided. Results: Methylome analysis identified coordinated CpG island hypermethylation in IDH1 MUT gliomas, consistent with previous reports. RBP1, important in retinoic acid metabolism, was found to be hypermethylated in 76 of 79 IDH1 MUT, 3 of 3 IDH2 MUT, and 0 of 116 IDH1/IDH2 WT tumors. IDH1/IDH2 mutation was highly correlated with RBP1 hypermethylation (n = 198; Spearman R = 0.94, 95% confidence interval = 0.92 to 0.95, P < .001). The Cancer Genome Atlas showed IDH1 MUT tumors (n = 23) to be RBP1-hypermethylated with decreased RBP1 expression compared with WT tumors (n = 124). Among patients with primary glioblastoma, patients with RBP1-unmethylated tumors (n = 102) had decreased median overall survival compared with patients with RBP1-methylated tumors (n = 22) (20.3 months vs 36.8 months, respectively; hazard ratio of death = 2.48, 95% confidence interval = 1.30 to 4.75, P = .006). Conclusion: RBP1 promoter hypermethylation is found in nearly all IDH1 and IDH2 mutant gliomas and is associated with improved patient survival. Because RBP1 is involved in retinoic acid synthesis, our results suggest that dysregulation of retinoic acid metabolism may contribute to glioma formation along the IDH1/IDH2-mutant pathway.
MeSH term(s)	Adult ; Aged ; Biomarkers, Tumor/genetics ; Blotting, Western ; Brain Neoplasms/chemistry ; Brain Neoplasms/genetics ; CpG Islands/genetics ; DNA Methylation ; DNA Mutational Analysis/methods ; Female ; Gene Expression Profiling ; Glioma/chemistry ; Glioma/genetics ; Humans ; Isocitrate Dehydrogenase/genetics ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Mutation ; Promoter Regions, Genetic/genetics ; Proportional Hazards Models ; Real-Time Polymerase Chain Reaction ; Restriction Mapping ; Retinol-Binding Proteins, Cellular/analysis ; Retinol-Binding Proteins, Cellular/genetics ; Retrospective Studies ; Reverse Transcriptase Polymerase Chain Reaction ; Sulfites/metabolism ; Tretinoin/metabolism
Chemical Substances	Biomarkers, Tumor ; RBP1 protein, human ; Retinol-Binding Proteins, Cellular ; Sulfites ; Tretinoin (5688UTC01R) ; IDH2 protein, human (EC 1.1.1.41) ; Isocitrate Dehydrogenase (EC 1.1.1.41) ; IDH1 protein, human (EC 1.1.1.42.) ; hydrogen sulfite (OJ9787WBLU)
Language	English
Publishing date	2012-09-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2992-0
ISSN	1460-2105 ; 0027-8874 ; 0198-0157
ISSN (online)	1460-2105
ISSN	0027-8874 ; 0198-0157
DOI	10.1093/jnci/djs357
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Full text online

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Order via subito

More links

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Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito