ORCID Profile
0000-0003-0391-0352
Current Organisations
The University of Edinburgh
,
University of Gdańsk
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Publisher: Springer Science and Business Media LLC
Date: 05-09-2016
DOI: 10.1038/NG.3659
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41586-020-1969-6
Abstract: Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale 1–3 . Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution in acral melanoma, for ex le, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter 4 identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation 5,6 analyses timings and patterns of tumour evolution 7 describes the erse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity 8,9 and evaluates a range of more-specialized features of cancer genomes 8,10–18 .
Publisher: Bentham Science Publishers Ltd.
Date: 11-09-2019
DOI: 10.2174/0929866526666190318101054
Abstract: Human proteome contains a plethora of short linear peptide motifs that is crucial for signaling and other cellular processes. These motifs are difficult to identify due to lack of systematic approach for their detection. Here we demonstrate the use of peptide phage display in combination with high throughput next generation sequencing to identify enriched peptide sequences through biopanning process against polo box domain (PBD) of mitotic polo like kinase 1 (Plk1). Purified recombinant Plk1 and two unrelated controls namely B-lymphocyte antigen (CD20) and fluorescent protein (mCherry) were subjected to peptide phage display analysis. Bacterially-propagated phage DNA was lified by PCR using triplet bar coded primers to tag the pool from each licon. Proteomic peptide phage display along with next generation sequencing and Bioinformatics analysis demonstrated several known and putative novel interactions which were potentially related to Plk1-PBD. With our strategy, we were able to identify and characterize several Plk1-PBD binding peptides, as well as define more precisely, consensus sequences. We believe that this information could provide valuable tools for exploring novel interaction involved in Plk1 signaling as well as to choose peptides for Plk1 specific drug development.
Publisher: Bentham Science Publishers Ltd.
Date: 20-12-2019
DOI: 10.2174/1568009619666190211113722
Abstract: The rapid expansion of genome-wide profiling techniques offers the opportunity to utilize various types of information collected in the study of human health and disease. Overexpression of Polo like kinase 1 (PLK1) is associated with esophageal adenocarcinoma (OAC), however biological functions and molecular targets of PLK1 in OAC are still unknown. Here we performed integrative analysis of two “omics” data sources to reveal high-level interactions of PLK1 associated with OAC. Initially, quantitative gene expression (RPKM) was measured from transcriptomics data set of four OAC patients. In parallel, alteration in phosphorylation levels was evaluated in the proteomics data set (mass spectrometry) in OAC cell line (PLK1 inhibited). Next, two “omics” data sets were integrated and through comprehensive analysis possible true PLK1 targets that may serve as OAC biomarkers were assembled. Through experimental validation, small ubiquitin-related modifier 1 (SUMO1) and heat shock protein beta-1 (HSPB1) were identified as novel phosphorylation targets of PLK1. Consequently in vivo, in situ and in silico experiments clearly demonstrated the interaction of PLK1 with putative novel targets (SUMO1 and HSPB1). Identification of a PLK1 dependent biosignature in OAC with high confidence in two omics levels proven the robustness and efficacy of our integrative approach.
Publisher: Elsevier BV
Date: 05-2020
Publisher: Bentham Science Publishers Ltd.
Date: 07-05-2021
DOI: 10.2174/0929866527999200901201837
Abstract: Oesophgeal adenocarcinoma (OAC) is the most frequent cause of cancer death. POLO-like kinase 1 (PLK1) is overexpressed in broad spectrum of tumors and has prognostic value in many cancers including esophageal cancer, suggesting its potential as a therapeutic target. p53, the guardian of genome is the most important tumor suppressors that represses the promoter of PLK1, whereas tumor cells with inactive p53 are arrested in mitosis due to DNA damage. PLK1 expression has been linked to the elevated p53 expression and has been shown to act as a biomarker that predicts poor prognosis in OAC. The aim of the present study was identification of PLK1 associated phosphorylation targets in p53 mutant and p53 normal cells to explore the downstream signaling evets. Here we develop a proof-of-concept phospho-proteomics approach to identify possible biomarkers that can be used to identify mutant p53 or wild-type p53 pathways. We treated PLK1 asynchronously followed by mass spectrometry data analysis. Protein networking and motif analysis tools were used to identify the significant clusters and potential biomarkers. We investigated approximately 1300 potential PLK1-dependent phosphopeptides by LCMS/ MS. In total, 2216 and 1155 high confidence phosphosites were identified in CP-A (p53+) and OE33 (p53-) cell lines owing to PLK1 inhibition. Further clustering and motif assessment uncovered many significant biomarkers with known and novel link to PLK1. Taken together, our study suggests that PLK1 may serve as a potential therapeutic target in human OAC. The data highlight the efficacy and specificity of small molecule PLK1 kinase inhibitors to identify novel signaling pathways in vivo.
Publisher: Wiley
Date: 09-2016
Abstract: Drugs targeting MDM2's hydrophobic pocket activate p53. However, these agents act allosterically and have agonist effects on MDM2's protein interaction landscape. Dominant p53-independent MDM2-drug responsive-binding proteins have not been stratified. We used as a variable the differential expression of MDM2 protein as a function of cell density to identify Nutlin-3 responsive MDM2-binding proteins that are perturbed independent of cell density using SWATH-MS. Dihydrolipoamide dehydrogenase, the E3 subunit of the mitochondrial pyruvate dehydrogenase complex, was one of two Nutlin-3 perturbed proteins identified fours hour posttreatment at two cell densities. Immunoblotting confirmed that dihydrolipoamide dehydrogenase was induced by Nutlin-3. Depletion of MDM2 using siRNA also elevated dihydrolipoamide dehydrogenase in Nutlin-3 treated cells. Mitotracker confirmed that Nutlin-3 inhibits mitochondrial activity. Enrichment of mitochondria using TOM22+ immunobeads and TMT labeling defined key changes in the mitochondrial proteome after Nutlin-3 treatment. Proximity ligation identified rearrangements of cellular protein-protein complexes in situ. In response to Nutlin-3, a reduction of dihydrolipoamide dehydrogenase/dihydrolipoamide acetyltransferase protein complexes highlighted a disruption of the pyruvate dehydrogenase complex. This coincides with an increase in MDM2/dihydrolipoamide dehydrogenase complexes in the nucleus that was further enhanced by the nuclear export inhibitor Leptomycin B. The data suggest one therapeutic impact of MDM2 drugs might be on the early perturbation of specific protein-protein interactions within the mitochondria. This methodology forms a blueprint for biomarker discovery that can identify rearrangements of MDM2 protein-protein complexes in drug-treated cells.
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.CELLSIG.2014.02.011
Abstract: Linear motifs mediate protein-protein interactions (PPI) that allow expansion of a target protein interactome at a systems level. This study uses a proteomics approach and linear motif sub-stratifications to expand on PPIs of MDM2. MDM2 is a multi-functional protein with over one hundred known binding partners not stratified by hierarchy or function. A new linear motif based on a MDM2 interaction consensus is used to select novel MDM2 interactors based on Nutlin-3 responsiveness in a cell-based proteomics screen. MDM2 binds a subset of peptide motifs corresponding to real proteins with a range of allosteric responses to MDM2 ligands. We validate cyclophilin B as a novel protein with a consensus MDM2 binding motif that is stabilised by Nutlin-3 in vivo, thus identifying one of the few known interactors of MDM2 that is stabilised by Nutlin-3. These data invoke two modes of peptide binding at the MDM2 N-terminus that rely on a consensus core motif to control the equilibrium between MDM2 binding proteins. This approach stratifies MDM2 interacting proteins based on the linear motif feature and provides a new biomarker assay to define clinically relevant Nutlin-3 responsive MDM2 interactors.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Ted Hupp.