Now showing items 1-20 of 24

    • A critical evaluation of the approaches to targeted protein degradation for drug discovery. 

      Chopra, R; Sadok, A; Collins, I (2019-04)
      There is a great deal of excitement around the concept of targeting proteins for degradation as an alternative to conventional inhibitory small molecules and antibodies. Protein degradation can be undertaken by bifunctional ...
    • An E2-ubiquitin thioester-driven approach to identify substrates modified with ubiquitin and ubiquitin-like molecules. 

      Bakos, G; Yu, L; Gak, IA; Roumeliotis, TI; Liakopoulos, D; Choudhary, JS; Mansfeld, J (2018-11-14)
      Covalent modifications of proteins with ubiquitin and ubiquitin-like molecules are instrumental to many biological processes. However, identifying the E3 ligase responsible for these modifications remains a major bottleneck ...
    • Cells Lacking the <i>RB1</i> Tumor Suppressor Gene Are Hyperdependent on Aurora B Kinase for Survival. 

      Oser, MG; Fonseca, R; Chakraborty, AA; Brough, R; Spektor, A; Jennings, RB; Flaifel, A; Novak, JS; Gulati, A; Buss, E; Younger, ST; McBrayer, SK; Cowley, GS; Bonal, DM; Nguyen, Q-D; Brulle-Soumare, L; Taylor, P; Cairo, S; Ryan, CJ; Pease, EJ; Maratea, K; Travers, J; Root, DE; Signoretti, S; Pellman, D; Ashton, S; Lord, CJ; Barry, ST; Kaelin, WG (2019-02)
      Small cell lung cancer (SCLC) accounts for 15% of lung cancers and is almost always linked to inactivating <i>RB1</i> and <i>TP53</i> mutations. SCLC frequently responds, albeit briefly, to chemotherapy. The canonical ...
    • CHD7 and 53BP1 regulate distinct pathways for the re-ligation of DNA double-strand breaks. 

      Rother, MB; Pellegrino, S; Smith, R; Gatti, M; Meisenberg, C; Wiegant, WW; Luijsterburg, MS; Imhof, R; Downs, JA; Vertegaal, ACO; Huet, S; Altmeyer, M; van Attikum, H (2020-11-13)
      Chromatin structure is dynamically reorganized at multiple levels in response to DNA double-strand breaks (DSBs). Yet, how the different steps of chromatin reorganization are coordinated in space and time to differentially ...
    • Genome-wide association study identifies multiple susceptibility loci for multiple myeloma. 

      Mitchell, JS; Li, N; Weinhold, N; Försti, A; Ali, M; van Duin, M; Thorleifsson, G; Johnson, DC; Chen, B; Halvarsson, B-M; Gudbjartsson, DF; Kuiper, R; Stephens, OW; Bertsch, U; Broderick, P; Campo, C; Einsele, H; Gregory, WA; Gullberg, U; Henrion, M; Hillengass, J; Hoffmann, P; Jackson, GH; Johnsson, E; Jöud, M; Kristinsson, SY; Lenhoff, S; Lenive, O; Mellqvist, U-H; Migliorini, G; Nahi, H; Nelander, S; Nickel, J; Nöthen, MM; Rafnar, T; Ross, FM; da Silva Filho, MI; Swaminathan, B; Thomsen, H; Turesson, I; Vangsted, A; Vogel, U; Waage, A; Walker, BA; Wihlborg, A-K; Broyl, A; Davies, FE; Thorsteinsdottir, U; Langer, C; Hansson, M; Kaiser, M; Sonneveld, P; Stefansson, K; Morgan, GJ; Goldschmidt, H; Hemminki, K; Nilsson, B; Houlston, RS (2016-07)
      Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power ...
    • Identification of highly penetrant Rb-related synthetic lethal interactions in triple negative breast cancer. 

      Brough, R; Gulati, A; Haider, S; Kumar, R; Campbell, J; Knudsen, E; Pettitt, SJ; Ryan, CJ; Lord, CJ (2018-10)
      Although defects in the RB1 tumour suppressor are one of the more common driver alterations found in triple-negative breast cancer (TNBC), therapeutic approaches that exploit this have not been identified. By integrating ...
    • Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.). 

      Gandhi, AK; Kang, J; Havens, CG; Conklin, T; Ning, Y; Wu, L; Ito, T; Ando, H; Waldman, MF; Thakurta, A; Klippel, A; Handa, H; Daniel, TO; Schafer, PH; Chopra, R (2014-03)
      Cereblon (CRBN), the molecular target of lenalidomide and pomalidomide, is a substrate receptor of the cullin ring E3 ubiquitin ligase complex, CRL4(CRBN) . T cell co-stimulation by lenalidomide or pomalidomide is cereblon ...
    • Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma. 

      Mackay, A; Burford, A; Carvalho, D; Izquierdo, E; Fazal-Salom, J; Taylor, KR; Bjerke, L; Clarke, M; Vinci, M; Nandhabalan, M; Temelso, S; Popov, S; Molinari, V; Raman, P; Waanders, AJ; Han, HJ; Gupta, S; Marshall, L; Zacharoulis, S; Vaidya, S; Mandeville, HC; Bridges, LR; Martin, AJ; Al-Sarraj, S; Chandler, C; Ng, H-K; Li, X; Mu, K; Trabelsi, S; Brahim, DH-B; Kisljakov, AN; Konovalov, DM; Moore, AS; Carcaboso, AM; Sunol, M; de Torres, C; Cruz, O; Mora, J; Shats, LI; Stavale, JN; Bidinotto, LT; Reis, RM; Entz-Werle, N; Farrell, M; Cryan, J; Crimmins, D; Caird, J; Pears, J; Monje, M; Debily, M-A; Castel, D; Grill, J; Hawkins, C; Nikbakht, H; Jabado, N; Baker, SJ; Pfister, SM; Jones, DTW; Fouladi, M; von Bueren, AO; Baudis, M; Resnick, A; Jones, C (2017-10)
      We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating ...
    • Mind Bomb Regulates Cell Death during TNF Signaling by Suppressing RIPK1's Cytotoxic Potential. 

      Feltham, R; Jamal, K; Tenev, T; Liccardi, G; Jaco, I; Domingues, CM; Morris, O; John, SW; Annibaldi, A; Widya, M; Kearney, CJ; Clancy, D; Elliott, PR; Glatter, T; Qiao, Q; Thompson, AJ; Nesvizhskii, A; Schmidt, A; Komander, D; Wu, H; Martin, S; Meier, P (2018-04)
      Tumor necrosis factor (TNF) is an inflammatory cytokine that can signal cell survival or cell death. The mechanisms that switch between these distinct outcomes remain poorly defined. Here, we show that the E3 ubiquitin ...
    • Molecular alterations in triple-negative breast cancer-the road to new treatment strategies. 

      Denkert, C; Liedtke, C; Tutt, A; von Minckwitz, G (2017-06)
      Triple-negative breast cancer is a heterogeneous disease and specific therapies have not been available for a long time. Therefore, conventional chemotherapy is still considered the clinical state of the art. Different ...
    • Molecular basis of APC/C regulation by the spindle assembly checkpoint. 

      Alfieri, C; Chang, L; Zhang, Z; Yang, J; Maslen, S; Skehel, M; Barford, D (2016-08-10)
      In the dividing eukaryotic cell, the spindle assembly checkpoint (SAC) ensures that each daughter cell inherits an identical set of chromosomes. The SAC coordinates the correct attachment of sister chromatid kinetochores ...
    • PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation. 

      Gupta, A; Anjomani-Virmouni, S; Koundouros, N; Dimitriadi, M; Choo-Wing, R; Valle, A; Zheng, Y; Chiu, Y-H; Agnihotri, S; Zadeh, G; Asara, JM; Anastasiou, D; Arends, MJ; Cantley, LC; Poulogiannis, G (2017-03)
      PARK2 is a gene implicated in disease states with opposing responses in cell fate determination, yet its contribution in pro-survival signaling is largely unknown. Here we show that PARK2 is altered in over a third of all ...
    • PARP inhibitors: Synthetic lethality in the clinic. 

      Lord, CJ; Ashworth, A (2017-03-16)
      PARP inhibitors (PARPi), a cancer therapy targeting poly(ADP-ribose) polymerase, are the first clinically approved drugs designed to exploit synthetic lethality, a genetic concept proposed nearly a century ago. Tumors ...
    • Prostate Cancer Germline Variations and Implications for Screening and Treatment. 

      Dias, A; Kote-Jarai, Z; Mikropoulos, C; Eeles, R (2018-09-04)
      Prostate cancer (PCa) is a highly heritable disease, and rapid evolution of sequencing technologies has enabled marked progression of our understanding of its genetic inheritance. A complex polygenic model that involves ...
    • Proteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12. 

      Khan, OM; Almagro, J; Nelson, JK; Horswell, S; Encheva, V; Keyan, KS; Clurman, BE; Snijders, AP; Behrens, A (2021-04-06)
      The tumour suppressor FBW7 is a substrate adaptor for the E3 ubiquitin ligase complex SKP1-CUL1-F-box (SCF), that targets several oncoproteins for proteasomal degradation. FBW7 is widely mutated and FBW7 protein levels are ...
    • RavN is a member of a previously unrecognized group of Legionella pneumophila E3 ubiquitin ligases. 

      Lin, Y-H; Lucas, M; Evans, TR; Abascal-Palacios, G; Doms, AG; Beauchene, NA; Rojas, AL; Hierro, A; Machner, MP (2018-02-07)
      The eukaryotic ubiquitylation machinery catalyzes the covalent attachment of the small protein modifier ubiquitin to cellular target proteins in order to alter their fate. Microbial pathogens exploit this post-translational ...
    • RB1 Heterogeneity in Advanced Metastatic Castration-Resistant Prostate Cancer. 

      Nava Rodrigues, D; Casiraghi, N; Romanel, A; Crespo, M; Miranda, S; Rescigno, P; Figueiredo, I; Riisnaes, R; Carreira, S; Sumanasuriya, S; Gasperini, P; Sharp, A; Mateo, J; Makay, A; McNair, C; Schiewer, M; Knudsen, K; Boysen, G; Demichelis, F; de Bono, JS (2019-01)
      Purpose Metastatic castration-resistant prostate cancer (mCRPC) is a lethal but clinically heterogeneous disease, with patients having variable benefit from endocrine and cytotoxic treatments. Intrapatient genomic heterogeneity ...
    • RNAi screen reveals synthetic lethality between cyclin G-associated kinase and FBXW7 by inducing aberrant mitoses. 

      Dolly, SO; Gurden, MD; Drosopoulos, K; Clarke, P; de Bono, J; Kaye, S; Workman, P; Linardopoulos, S (2017-09)
      Background F-box and WD40 repeat domain-containing 7 (FBXW7) is an E3 ubiquitin ligase involved in the ubiquitination and degradation of multiple oncogenic substrates. The tumour suppressor function is frequently lost in ...
    • Structural basis of Cullin 2 RING E3 ligase regulation by the COP9 signalosome. 

      Faull, SV; Lau, AMC; Martens, C; Ahdash, Z; Hansen, K; Yebenes, H; Schmidt, C; Beuron, F; Cronin, NB; Morris, EP; Politis, A (2019-08-23)
      Cullin-Ring E3 Ligases (CRLs) regulate a multitude of cellular pathways through specific substrate receptors. The COP9 signalosome (CSN) deactivates CRLs by removing NEDD8 from activated Cullins. Here we present structures ...
    • SUMO-mediated regulation of NLRP3 modulates inflammasome activity. 

      Barry, R; John, SW; Liccardi, G; Tenev, T; Jaco, I; Chen, C-H; Choi, J; Kasperkiewicz, P; Fernandes-Alnemri, T; Alnemri, E; Drag, M; Chen, Y; Meier, P (2018-08)
      The NLRP3 inflammasome responds to infection and tissue damage, and rapidly escalates the intensity of inflammation by activating interleukin (IL)-1β, IL-18 and cell death by pyroptosis. How the NLRP3 inflammasome is ...