A5078351589- Cancer, Hypoxia, and Metabolism
- Fibroblast Growth Factor Research
- Epigenetics and DNA Methylation
- RNA modifications and cancer
- Kruppel-like factors research
- Metal-Catalyzed Oxygenation Mechanisms
- Cancer-related Molecular Pathways
- Protein Kinase Regulation and GTPase Signaling
- High Altitude and Hypoxia
- Cell death mechanisms and regulation
- RNA and protein synthesis mechanisms
- Cellular transport and secretion
- Peroxisome Proliferator-Activated Receptors
- Adipose Tissue and Metabolism
- Immune Cell Function and Interaction
- Heme Oxygenase-1 and Carbon Monoxide
- Eicosanoids and Hypertension Pharmacology
- Hippo pathway signaling and YAP/TAZ
- Cardiomyopathy and Myosin Studies
- Cancer-related gene regulation
- Immune cells in cancer
- Genetics and Neurodevelopmental Disorders
- Mitochondrial Function and Pathology
- Parasites and Host Interactions
- Melanoma and MAPK Pathways
University of Birmingham
2015-2024
Genomics (United Kingdom)
2023-2024
University of Oxford
2006-2019
Tuskegee University
2010
Center for Cancer Research
2010
Centre for Human Genetics
2005-2009
University of Pennsylvania
2003-2005
UPMC Hillman Cancer Center
2003-2005
Cancer Research Institute
2003-2005
Institute of Cancer Research
2001-2003
Studies on hypoxia-sensitive pathways have revealed a series of Fe(II)-dependent dioxygenases that regulate hypoxia-inducible factor (HIF) by prolyl and asparaginyl hydroxylation. The recognition these unprecedented signaling processes has led to search for other substrates the HIF hydroxylases. Here we show human hydroxylase, inhibiting (FIH), also efficiently hydroxylates specific (Asn)-residues within proteins IkappaB family. After identification ankyrin repeat domain (ARD)-containing in...
The stability and activity of hypoxia-inducible factor (HIF) are regulated by the post-translational hydroxylation specific prolyl asparaginyl residues. We show that HIF hydroxylase, inhibiting (FIH), also catalyzes highly conserved residues within ankyrin repeat (AR) domains (ARDs) endogenous Notch receptors. AR decreases extent ARD binding to FIH while not affecting signaling through canonical pathway. proteins were found efficiently compete with for FIH-dependent hydroxylation....
Membrane blebbing during the apoptotic execution phase results from caspase-mediated cleavage and activation of ROCK I. Here, we show that activity, myosin light chain (MLC) phosphorylation, MLC ATPase an intact actin cytoskeleton, but not microtubular are required for disruption nuclear integrity apoptosis. Inhibition or which protect integrity, does affect degradation proteins such as lamins A, B1, C. The conditional I was sufficient to tear apart nuclei in lamin A/C null fibroblasts,...
Mutations of human PHF8 cluster within its JmjC encoding exons and are linked to mental retardation (MR) a cleft lip/palate phenotype. Sequence comparisons, employing structural insights, suggest that contains the double stranded beta-helix fold ferrous iron binding residues present in 2-oxoglutarate-dependent oxygenases. We report recombinant is an Fe(II) N(epsilon)-methyl lysine demethylase, which acts on histone substrates. selective vitro for N(epsilon)-di- mono-methylated does not...
Significance Members of the 2-oxoglutarate (2OG)-dependent oxygenase superfamily catalyze a range important biological oxidations. Structurally informed bioinformatic predictions suggest that human genome encodes as yet unassigned members superfamily. We describe work demonstrating 2OG and Fe(II)-dependent domain-containing protein 1 (OGFOD1) is hydroxylase modifies small ribosomal subunit RPS23 at conserved prolyl residue in ribosome-decoding center suppression or deletion OGFOD1 associated...
Efficient stop codon recognition and peptidyl-tRNA hydrolysis are essential in order to terminate translational elongation maintain protein sequence fidelity. Eukaryotic termination is mediated by a release factor complex that includes eukaryotic 1 (eRF1) eRF3. The N terminus of eRF1 contains highly conserved motifs couple at the ribosomal A site hydrolysis. We reveal Jumonji domain-containing 4 (Jmjd4), 2-oxoglutarate- Fe(II)-dependent oxygenase, catalyzes carbon (C4) lysyl hydroxylation...
Abstract BRAF mutations result in constitutively active kinase activity and increased extracellular signal-regulated (ERK) signaling cell proliferation. Initial studies have shown that occur at a high frequency melanocytic nevi metastatic lesions, but recent data revealed much lower incidence of these early-stage melanoma, implying other factors may contribute to melanoma pathogenesis wild-type (WT) context. To identify such contributing factors, we used microarray gene expression profiling...
Factor-inhibiting hypoxia-inducible factor (FIH) catalyzes the β-hydroxylation of an asparagine residue in C-terminal transcriptional activation domain hypoxia inducible (HIF), a modification that negatively regulates HIF activity. FIH also hydroxylation highly conserved Asn residues within ubiquitous ankyrin repeat (ARD)-containing proteins. Hydroxylation has been shown to stabilize localized regions ARD fold case three-repeat consensus protein, but this phenomenon not demonstrated for...
Hypoxia signaling influences tumor development through both cell-intrinsic and -extrinsic pathways. Inhibiting hypoxia-inducible factor (HIF) function has recently been approved as a cancer treatment strategy. Hence, it is important to understand how regulators of HIF may affect growth under physiological conditions. Here we report that in aging mice factor-inhibiting (FIH), one the most studied negative HIF, haploinsufficient suppressor spontaneous B cell lymphomas, particular pulmonary...
Post-translational modifications on histones are an important mechanism for the regulation of gene expression and involved in all aspects cell growth differentiation, as well pathological processes including neurodegeneration, autoimmunity, cancer. A major challenge within chromatin field is to develop methods quantitative analysis histone modifications. Here we report a mass spectrometry (MS) approach based ultraperformance liquid chromatography high/low collision switching (UPLC-MS(E))...
Hypoxia-inducible transcription factors (HIFs) directly dictate the expression of multiple RNA species including novel and as yet uncharacterized long noncoding transcripts with unknown function. We used pan-genomic HIF-binding transcriptomic data to identify a Noncoding Intergenic Co-Induced transcript (NICI) on chromosome 12p13.31 which is regulated by hypoxia via HIF-1 promoter-binding in cell types. CRISPR/Cas9-mediated deletion hypoxia-response element revealed co-regulation NICI...
Physiological effects of cellular hypoxia are sensed by prolyl hydroxylase (PHD) enzymes which regulate HIFs. Genetic interventions on HIF/PHD pathways reveal multiple phenotypes that extend the known biology hypoxia. Recent studies unexpectedly implicate HIF in aspects immune and inflammatory pathways. However such often limited systemic lethal and/or use tissue-specific recombination systems, inherently irreversible, un-physiologically restricted difficult to time. To study these processes...
Ankyrin repeats (ARs) are one of the most common structural motifs among eukaryotic proteins. Recent analyses have shown that factor inhibiting hypoxia-inducible (FIH) catalyses hydroxylation highly conserved Asn-residues within ankyrin repeat domains (ARDs). However, effect Asn-hydroxylation on ARD structure is unknown. Supporting proposal FIH-mediated ubiquitous we report consensus proteins FIH substrates both in vitro and vivo. X-ray diffraction revealed does not alter archetypical...