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Amelio I.,Medical Research Council Toxicology Unit | Inoue S.,Ontario Cancer Institute | Markert E.K.,Institute for Advanced Study | Levine A.J.,Institute for Advanced Study | And 4 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activation are associated with cancer progression. Here, we demonstrate that the transcription factor TAp73 opposes HIF-1 activity through a nontranscriptional mechanism, thus affecting tumor angiogenesis. TAp73-deficient mice have an increased incidence of spontaneous and chemically induced tumors that also display enhanced vascularization. Mechanistically, TAp73 interacts with the regulatory subunit (α) of HIF-1 and recruits mouse double minute 2 homolog into the protein complex, thus promoting HIF-1α polyubiquitination and consequent proteasomal degradation in an oxygen-independent manner. In human lung cancer datasets, TAp73 strongly predicts good patient prognosis, and its expression is associated with low HIF-1 activation and angiogenesis. Our findings, supported by in vivo and clinical evidence, demonstrate a mechanism for oxygen-independent HIF-1 regulation, which has important implications for individualizing therapies in patients with cancer. © 2014, National Academy of Sciences. All rights reserved.


Davies J.W.,Royal Infirmary | Hainsworth A.H.,St George's, University of London | Hainsworth A.H.,De Montfort University | Guerin C.J.,Medical Research Council Toxicology Unit | Lambert D.G.,Royal Infirmary
British Journal of Anaesthesia | Year: 2010

Background. Transient receptor potential vanilloid subtype 1 (TRPV1) receptor is a primary pain-sensing relay at peripheral sensory nerve endings and is also widespread in the brain, where it is implicated in neurodegeneration. Previous studies of TRPV1 neurotoxicity have utilized heterogeneous receptor populations, non-selective ligands, or non-neuronal cell types. Here, we explored the pharmacology of TRPV1-induced cytotoxicity in a homogeneous, neurone-like cellular environment.Methods. Cell death was examined in a human neurone-like cell line, stably expressing recombinant human TRPV1. Cytotoxicity was quantified in terms of nuclear morphology and mitochondrial complex II activity. Immunocytochemical markers of apoptotic cell death were also examined.Results. The TRPV1-selective agonist capsaicin, and the endovanilloids anandamide and N-arachidonoyl-dopamine (NADA), induced TRPV1-dependent delayed cell death in a concentration- and time-dependent manner. Capsaicin exposure time was significantly correlated with potency (r2=0.91, P=0.01). Release of cytochrome c from mitochondria, activation of caspase-3, and condensed nuclear chromatin were evident 6 h after capsaicin exposure, but cytotoxicity was unaffected by a pan-caspase inhibitor (zVAD-fmk, 50 μM).Conclusions. We conclude that capsaicin, anandamide, and NADA can initiate TRPV1-dependent delayed cell death in neurone-like cells. This is an apoptosis-like process, but independent of caspase activity. © The Author [2010]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.


A team of scientists at the University of Leicester have discovered a drug for Alzheimer's disease that not only improves the neurodegenerative symptoms but also extends the life span of terminally ill mice. The team of international researchers based at the Medical Research Council Toxicology Unit in UL conducted a four-year study in mice to find a new drug that targets a particular protein in the brain of Alzheimer's disease patients. The study deals with discovery of a novel drug-like molecules that help in retrieving the loss of memory and slowing down the degeneration of brain in mice. It has the potential to treat AD in humans, said Andrew Tobin, the corresponding author of the study, and Dr. Sophie Bradley, the lead researcher of the study. For the purpose of the study, the investigators used mice with degenerating brain cells that mimic the brain of humans with AD. The researchers concentrated on a protein that is previously known to be associated with AD, which they believed could be a potential drug target. It was observed that when terminally ill mice were treated with novel drugs that are aimed at the specific protein in the brain, the animals not only exhibited improvement in neurodegenerative symptoms but also had an extended life span. A number of studies conducted earlier used a variety of drugs that targeted the particular protein in brain and found that in spite of providing improvements in cognitive functions, they also resulted in severe side effects. In contrast, the drug named allosteric ligands that is used in the current study did not result in any adverse effect on mice when they attacked M1 muscarinic receptor, the target protein in the brain. When the above receptor in the brain is activated by the drug, the mice showed great improvement in cognitive functions, symptoms of brain degeneration, and life span. The study findings are of great value in understanding whether M1 muscarinic receptor is a "viable drug target" for developing reliable treatment options against AD. As a matter of fact, there are no effective treatments for the debilitating dementia, as all the intervention methods available in the market are aimed at masking the symptoms of the disease. "Our study opens up avenues for researchers to look at new drugs that treat the symptoms of Alzheimer's and also slow disease progression," noted Tobin in a press release. The study is published in The Journal of Clinical Investigation. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.


Muller P.A.J.,Medical Research Council Toxicology Unit | Vousden K.H.,CR UK Beatson Institute
Cancer Cell | Year: 2014

Many different types of cancer show a high incidence of TP53 mutations, leading to the expression of mutant p53 proteins. There is growing evidence that these mutant p53s have both lost wild-type p53 tumor suppressor activity and gained functions that help to contribute to malignant progression. Understanding the functions of mutant p53 will help in the development of new therapeutic approaches that may be useful in a broad range of cancer types. © 2014 The Authors.


Knight R.A.,Medical Research Council Toxicology Unit | Gostev M.,Technological University | Ilisavskii S.,Technological University | Willis A.E.,Medical Research Council Toxicology Unit | And 3 more authors.
Oncotarget | Year: 2014

Understanding therapeutic mechanisms of drug anticancer cytotoxicity represents a key challenge in preclinical testing. Here we have performed a meta-analysis of publicly available tumor cell line growth inhibition assays (~ 70 assays from 6 independent experimental groups covering ~ 500 000 molecules) with the primary goal of understanding molecular therapeutic mechanisms of cancer cytotoxicity. To implement this we have collected currently available information on protein targets for molecules that were tested in the assays. We used a statistical methodology to identify protein targets overrepresented among molecules exhibiting cancer cytotoxicity with the particular focus of identifying overrepresented patterns consisting of several proteins (i.e. proteins "A" and "B" and "C"). Our analysis demonstrates that targeting individual proteins can result in a significant increase (up to 50-fold) of the observed odds for a molecule to be an efficient inhibitor of tumour cell line growth. However, further insight into potential molecular mechanisms reveals a multi-target mode of action: targeting a pattern of several proteins drastically increases the observed odds (up to 500-fold) for a molecule to be tumour cytotoxic. In contrast, molecules targeting only one protein but not targeting an additional set of proteins tend to be nontoxic. Our findings support a poly-pharmacology drug discovery paradigm, demonstrating that anticancer cytotoxicity is a product, in most cases, of multi-target mode of drug action.


Jackson T.J.,Medical Research Council Toxicology Unit | Jackson T.J.,University of Nottingham | Spriggs R.V.,Medical Research Council Toxicology Unit | Burgoyne N.J.,Medical Research Council Toxicology Unit | And 2 more authors.
BMC Genomics | Year: 2014

Background: Next-generation sequencing does not yield fully unbiased estimates for read abundance, which may impact on the conclusions that can be drawn from sequencing data. The ligation step in RNA sequencing library generation is a known source of bias, motivating developments in enzyme technology and library construction protocols. We present the first comparison of the standard duplex adaptor protocol supplied by Life Technologies for use on the Ion Torrent PGM with an alternate single adaptor approach involving CircLigase (CircLig protocol).A correlation between over-representation in sequenced libraries and degree of secondary structure has been reported previously, therefore we also investigated whether bias could be reduced by ligation with an enzyme that functions at a temperature not permissive for such structure.Results: A pool of small RNA fragments of known composition was converted into a sequencing library using one of three protocols and sequenced on an Ion Torrent PGM. The CircLig protocol resulted in less over-representation of specific sequences than the standard protocol. Over-represented sequences are more likely to be predicted to have secondary structure and to co-fold with adaptor sequences. However, use of the thermostable ligase Methanobacterium thermoautotrophicum RNA ligase K97A (Mth K97A) was not sufficient to reduce bias.Conclusions: The single adaptor CircLigase-based approach significantly reduces, but does not eliminate, bias in Ion Torrent data. Ligases that function at temperatures to remove the possible influence of secondary structure on library generation may be of value, although Mth K97A is not effective in this case. © 2014 Jackson et al.


Spriggs K.A.,University of Nottingham | Bushell M.,Medical Research Council Toxicology Unit | Willis A.E.,Medical Research Council Toxicology Unit
Molecular Cell | Year: 2010

A number of stresses, including nutrient stress, temperature shock, DNA damage, and hypoxia, can lead to changes in gene expression patterns caused by a general shutdown and reprogramming of protein synthesis. Each of these stress conditions results in selective recruitment of ribosomes to mRNAs whose protein products are required for responding to stress. This recruitment is regulated by elements within the 5′ and 3′ untranslated regions of mRNAs, including internal ribosome entry segments, upstream open reading frames, and microRNA target sites. These elements can act singly or in combination and are themselves regulated by trans-acting factors. Translational reprogramming can result in increased life span, and conversely, deregulation of these translation pathways is associated with disease including cancer and diabetes. © 2010 Elsevier Inc.


Pichon X.,Medical Research Council Toxicology Unit | Wilson L.A.,Medical Research Council Toxicology Unit | Stoneley M.,Medical Research Council Toxicology Unit | Bastide A.,Medical Research Council Toxicology Unit | And 3 more authors.
Current Protein and Peptide Science | Year: 2012

A growing body of work demonstrates the importance of post-transcriptional control, in particular translation initiation, in the overall regulation of gene expression. Here we focus on the contribution of regulatory elements within the 5' and 3' untranslated regions of mRNA to gene expression in eukaryotic cells including terminal oligopyrimidine tracts, internal ribosome entry segments, upstream open reading frames and cytoplasmic polyadenylation elements. These mRNA regulatory elements may adopt complex secondary structures and/or contain sequence motifs that allow their interaction with a variety of regulatory proteins, RNAs and RNA binding proteins, particularly hnRNPs. The resulting interactions are context-sensitive, and provide cells with a sensitive and fast response to cellular signals such as hormone exposure or cytotoxic stress. Importantly, an increasing number of diseases have been identified, particularly cancers and those associated with neurodegeneration, which originate either from mutation of these regulatory motifs, or from deregulation of their cognate binding partners. © 2012 Bentham Science Publishers.


Somers J.,Medical Research Council Toxicology Unit | Poyry T.,Medical Research Council Toxicology Unit | Willis A.E.,Medical Research Council Toxicology Unit
International Journal of Biochemistry and Cell Biology | Year: 2013

Post-transcriptional control makes a major contribution to the overall regulation of gene expression pathway. Within the cytoplasm this is mediated by a combination of regulatory RNA motifs within the 5' and 3' untranslated regions of mRNAs and their interacting protein/RNA partners. One of the most common regulatory RNA elements in mammalian transcripts (present in approximately 40% of all mRNAs) are upstream open reading frames (uORFs). However, despite the prevalence of these RNA elements how they function is not well understood. In general, they act to repress translation of the physiological ORF under control conditions, and under certain pathophysiological stresses this repression can be alleviated. It is known that re-initiation following the translation of an uORF is utilised in some situations however there are numerous alternative mechanisms that control the synthesis of a protein whose mRNA contains uORFs. Moreover, the trans-acting factors that are also involved in this process are not well defined. In this review we summarise our current understanding of this area and highlight some common features of these RNA motifs that have been discovered to date. © 2013 The Authors. Published by Elsevier Ltd. All rights reserved.


The safety of chemicals, drugs, novel foods and genetically modified crops is often tested using repeat-dose sub-acute toxicity tests in rats or mice. It is important to avoid misinterpretations of the results as these tests are used to help determine safe exposure levels in humans. Treated and control groups are compared for a range of haematological, biochemical and other biomarkers which may indicate tissue damage or other adverse effects. However, the statistical analysis and presentation of such data poses problems due to the large number of statistical tests which are involved. Often, it is not clear whether a ''statistically significant'' effect is real or a false positive (type I error) due to sampling variation. The author's conclusions appear to be reached somewhat subjectively by the pattern of statistical significances, discounting those which they judge to be type I errors and ignoring any biomarker where the p-value is greater than p50.05. However, by using standardised effect sizes (SESs) a range of graphical methods and an over,all assessment of the mean absolute response can be made. The approach is an extension, not a replacement of existing methods. It is intended to assist toxicologists and regulators in the interpretation of the results. Here, the SES analysis has been applied to data from nine published sub-acute toxicity tests in order to compare the findings with those of the author's. Line plots, box plots and bar plots show the pattern of response. Dose-response relationships are easily seen. A ''bootstrap'' test compares the mean absolute differences across dose groups. In four out of seven papers where the no observed adverse effect level (NOAEL) was estimated by the authors, it was set too high according to the bootstrap test, suggesting that possible toxicity is under-estimated. ©2014 Michael F. W.

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