A5030123432- Ubiquitin and proteasome pathways
- Cancer-related Molecular Pathways
- Autophagy in Disease and Therapy
- Bone health and treatments
- Cancer, Hypoxia, and Metabolism
- Peptidase Inhibition and Analysis
- Advanced Proteomics Techniques and Applications
- Endoplasmic Reticulum Stress and Disease
- Glycosylation and Glycoproteins Research
- Click Chemistry and Applications
- Genetics and Neurodevelopmental Disorders
- Glioma Diagnosis and Treatment
- Reproductive Biology and Fertility
- Amyotrophic Lateral Sclerosis Research
- Parkinson's Disease Mechanisms and Treatments
- Ovarian function and disorders
- Alzheimer's disease research and treatments
- Biochemical and Molecular Research
- Bone and Joint Diseases
- Protein Degradation and Inhibitors
- NF-κB Signaling Pathways
- Mass Spectrometry Techniques and Applications
- Chemical Synthesis and Analysis
- Enzyme Structure and Function
- RNA modifications and cancer
University of Nottingham
2015-2024
Queen's Medical Centre
2012-2024
Brain Tumour Research
2022
The Graduate University for Advanced Studies, SOKENDAI
2022
The University of Notre Dame Australia
2020
Washtenaw Community College
2012
University of Michigan
2012
UiT The Arctic University of Norway
2012
Nottingham University Hospitals NHS Trust
2012
Nottingham Trent University
2007
We determined the effects of intravenous infusion amino acids (AA) at serum insulin 5, 30, 72, and 167 mU/l on anabolic signaling, expression ubiquitin-proteasome components, protein turnover in muscles healthy young men. Tripling AA availability 5 doubled incorporation [1-(13)C]leucine [i.e., muscle synthesis (MPS), P < 0.01] without affecting rate leg breakdown (LPB; appearance d(5)-phenylalanine). While keeping constant, increasing to 30 halved LPB (P 0.05) further inhibition higher...
Ubiquitin-positive intraneuronal inclusions are a consistent feature of the major human neurodegenerative diseases, suggesting that dysfunction ubiquitin proteasome system is central to disease etiology. Research using inhibitors 20S model Parkinson's controversial. We report for first time specifically 26S proteasomal sufficient trigger disease. Here, we describe novel conditional genetic mouse models Cre/loxP spatially restrict inactivation Psmc1 ( Rpt2/S4 ) neurons either substantia nigra...
Nrf2 regulates the expression of numerous cytoprotective genes in mammalian cells. The activity is regulated by Cul3 adaptor Keap1, yet little known regarding mechanisms regulation Keap1 itself. Here, we have used immunopurification and mass spectrometry, addition to immunoblotting, identify sequestosome 1 (SQSTM1) as a cellular binding partner Keap1. SQSTM1 serves scaffold various signaling pathways shuttles polyubiquitinated proteins proteasomal lysosomal degradation machineries. Ectopic...
α‐Synuclein has been implicated in the pathogenesis of Parkinson's disease based on mutations familial cases and its presence Lewy bodies. Here we show that over‐expression wild‐type human α‐synuclein is sufficient to induce inclusion formation SH‐SY5Y cells. In this cellular model, proteasome inhibition leads an increase accumulation vivo without ubiquitylation. accordance, find vitro, unmodified can be directly degraded by 20S proteasome. These findings suggest ubiquitin‐independent...
Alzheimer's disease is the most common cause of dementia in elderly. Although several genetic defects have been identified patients with a family history this disease, majority cases involve individuals no known predisposition. A mutant form ubiquitin, termed Ub(+1), has selectively observed brains patients, including those nonfamilial but it unclear why Ub(+1) expression should be deleterious. Here we show that an efficient substrate for polyubiquitination vitro and transfected human cells....
Abstract Filamentous inclusions composed of the microtubule‐associated protein tau are a defining characteristic large number neurodegenerative diseases. Here we show that degradation in stably transfected and non‐transfected SH‐SY5Y cells is blocked by irreversible proteasome inhibitor lactacystin. Further, find vitro , natively unfolded can be directly processed 20S without requirement for ubiquitylation, highly reproducible pattern intermediates readily detectable during this process....
Interactions of CNS cells lead to the establishment complex neural systems. Specifically, oligodendrocytes form myelin sheaths around axons that enable rapid electrical conduction impulses. Recent evidence has emerged may also release trophic factors promoting neuronal survival. We therefore studied effects released from oligodendrocyte lineage on survival and morphology neurons. Neurons derived rat embryonic cortices were cultured exposed media conditioned by precursor (OPCs) or...
The p62 protein functions as a scaffold in signaling pathways that lead to activation of NF-kappaB and is an important regulator osteoclastogenesis. Mutations affecting the receptor activator axis can result human skeletal disorders, including those identified C-terminal ubiquitin-associated (UBA) domain patients with Paget disease bone. These observations suggest may involve common mechanism related alterations ubiquitin-binding properties p62. structural basis for ubiquitin recognition by...
Growing evidence implicates impairment of autophagy as a candidate pathogenic mechanism in the spectrum neurodegenerative disorders which includes amyotrophic lateral sclerosis and frontotemporal lobar degeneration (ALS-FTLD). SQSTM1, encodes receptor SQSTM1/p62, is genetically associated with ALS-FTLD, although to date autophagy-relevant functional defects disease-associated variants have not been described. A key protein-protein interaction recognition lipid-anchored form LC3 (LC3-II)...
Mutations of SQSTM1 occur in about10% patients with Paget's disease bone (PDB), but it is unclear whether they play a causal role or regulate susceptibility to an environmental trigger. Here we show that mice proline leucine mutation at codon 394 mouse sqstm1 (P394L), equivalent the P392L humans, develop disorder remarkable similarity PDB. The P394L mutant developed focal lesions increasing age and by 12 months, 14/18 (77%) heterozygotes 20/21 (95%) homozygotes had lesions, compared 0/18...
Abstract Three novel missense mutations of SQSTM1 were identified in familial PDB, all affecting the UBA domain. Functional and structural analysis showed that disease severity was related to type mutation but unrelated polyubiquitin-binding properties mutant domain peptides. Introduction: Mutations ubiquitin-associated (UBA) Sequestosome 1 (SQSTM1) gene have recently been as a common cause Paget's bone (PDB), mechanisms responsible are unclear. We three conducted functional analyses...
p62 is a multi-functional protein, which induces nuclear factor-kappaB (NFkappaB) activation through multiple upstream signalling pathways, including those triggered by the epidermal growth factor (EGF) family of receptors. We hypothesised that overexpression increased EGF receptor expression and worse outcome in breast cancer would be associated. stained tissue microarray representing 523 cancers using commercial guinea pig anti-human sera standard immunohistochemical methods to address...
5-HT(6) receptors are abundant in the hippocampus, nucleus accumbens and striatum, supporting their role learning memory. Selective receptor antagonists produce pro-cognitive effects several memory paradigms while agonists have been found to enhance impair
<h3>Objectives</h3> Faecal serine proteases (FSPs) may play a role in irritable bowel syndrome with diarrhoea (IBS-D), but their origin is unclear. We aimed to structurally characterise them and define the impact of colonic cleansing transit time. <h3>Design</h3> samples were obtained from 30 healthy volunteers (HV) 79 patients IBS-D participating trial ondansetron versus placebo. Colonic was measured using radio-opaque markers. Samples also 24 HV before after osmotic laxative MoviPrep. FSPs...
Abstract Specific interactions between proteins and their binding partners are fundamental to life processes. The ability detect protein complexes, map sites of binding, is crucial understanding basic biology at the molecular level. Methods that employ sensitive analytical techniques such as mass spectrometry have potential provide valuable insights with very little material on short time scales. Here we present a differential footprinting technique employing an efficient photo-activated...