Publications
325 results found
Batty EC, Jensen K, Freemont PS, 2012, PML NUCLEAR BODIES AND OTHER TRIM-DEFINED SUBCELLULAR COMPARTMENTS, TRIM/RBCC PROTEINS, Vol: 770, Pages: 39-58, ISSN: 0065-2598
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- Citations: 7
Lossi NS, Dajani R, Freemont P, et al., 2011, Structure-function analysis of HsiF, a gp25-like component of the type VI secretion system, in <i>Pseudomonas aeruginosa</i>, MICROBIOLOGY-SGM, Vol: 157, Pages: 3292-3305, ISSN: 1350-0872
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- Citations: 40
Attia M, Foerster A, Rachez C, et al., 2011, Interaction between Nucleosome Assembly Protein 1-like Family Members, JOURNAL OF MOLECULAR BIOLOGY, Vol: 407, Pages: 647-660, ISSN: 0022-2836
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- Citations: 33
MacDonald JT, Barnes C, Kitney RI, et al., 2011, Computational design approaches and tools for synthetic biology, INTEGRATIVE BIOLOGY, Vol: 3, Pages: 97-108, ISSN: 1757-9694
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- Citations: 58
Russell RA, Adams NM, Stephens D, et al., 2011, Methodology for Quantitative Analysis of 3-D Nuclear Architecture, ADVANCES IN NUCLEAR ARCHITECTURE, Editors: Adams, Freemont, Publisher: SPRINGER-VERLAG BERLIN, Pages: 173-187, ISBN: 978-90-481-9898-6
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- Citations: 2
Adams NM, Freemont PS, 2010, Advances in Nuclear Architecture, Publisher: Springer Verlag, ISBN: 9789048198986
Heathcote DA, Patel H, Kroll SH, et al., 2010, A novel pyrazolo[1,5-a]pyrimidine is a potent inhibitor of cyclin-dependent protein kinases 1, 2, and 9, which demonstrates antitumor effects in human tumor xenografts following oral administration, J Med Chem, Vol: 53, Pages: 8508-8522
Cyclin-dependent protein kinases (CDKs) are central to the appropriate regulation of cell proliferation, apoptosis, and gene expression. Abnormalities in CDK activity and regulation are common features of cancer, making CDK family members attractive targets for the development of anticancer drugs. Here, we report the identification of a pyrazolo[1,5-a]pyrimidine derived compound, 4k (BS-194), as a selective and potent CDK inhibitor, which inhibits CDK2, CDK1, CDK5, CDK7, and CDK9 (IC= 3, 30, 30, 250, and 90 nmol/L, respectively). Cell-based studies showed inhibition of the phosphorylation of CDK substrates, Rb and the RNA polymerase II C-terminal domain, down-regulation of cyclins A, E, and D1, and cell cycle block in the S and G/M phases. Consistent with these findings, 4k demonstrated potent antiproliferative activity in 60 cancer cell lines tested (mean GI= 280 nmol/L). Pharmacokinetic studies showed that 4k is orally bioavailable, with an elimination half-life of 178 min following oral dosing in mice. When administered at a concentration of 25 mg/kg orally, 4k inhibited human tumor xenografts and suppressed CDK substrate phosphorylation. These findings identify 4k as a novel, potent CDK selective inhibitor with potential for oral delivery in cancer patients.
Akiyoshi T, Heathcote DA, Azzi J, et al., 2010, The Role of SPI6 in the Survival of Allograft Derived Dendritic Cells and Tolerance., AMERICAN JOURNAL OF TRANSPLANTATION, Vol: 10, Pages: 561-561, ISSN: 1600-6135
Ewens CA, Kloppsteck P, Foerster A, et al., 2010, Structural and functional implications of phosphorylation and acetylation in the regulation of the AAA+ protein p97, BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE, Vol: 88, Pages: 41-48, ISSN: 0829-8211
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- Citations: 30
Gulati S, Rouilly V, Niu X, et al., 2009, Opportunities for microfluidic technologies in synthetic biology, JOURNAL OF THE ROYAL SOCIETY INTERFACE, Vol: 6, ISSN: 1742-5689
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- Citations: 54
Xu Y, Liu M, Simpson PJ, et al., 2009, Automated Assignment in Selectively Methyl-Labeled Proteins, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Vol: 131, Pages: 9480-+, ISSN: 0002-7863
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- Citations: 27
Russell RA, Adams NM, Stephens DA, et al., 2009, Segmentation of Fluorescence Microscopy Images for Quantitative Analysis of Cell Nuclear Architecture, BIOPHYSICAL JOURNAL, Vol: 96, Pages: 3379-3389, ISSN: 0006-3495
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- Citations: 26
Lu D, Wörmann ME, Zhang X, et al., 2009, Structure-based mechanism of lipoteichoic acid synthesis by Staphylococcus aureus LtaS.
Batty E, Jensen K, Freemont P, 2009, PML nuclear bodies and their spatial relationships in the mammalian cell nucleus., Front Biosci (Landmark Ed), Vol: 14, Pages: 1182-1196
Promyelocytic leukaemia nuclear bodies (PML NBs) are found within the nucleus of mammalian cells, and are formed from the constituent proteins PML and Sp100. Numbering between 10 and 30 per cell, they are an obvious feature of the nuclear landscape, yet their functions have still to be unambiguously defined. In the mammalian nucleus, compartmentalization of functions is apparent, as reflected in the wide-range of other nuclear compartments that can be identified. These include nucleoli, transcription foci, splicing speckles, chromosomal topological markers such as centromeres and telomeres, the nuclear boundary, and the nucleoplasm itself. Quantification of the otherwise qualitative observations of relationships between mammalian nuclear compartments is essential for a complete understanding of nuclear processes. Here we describe some of the interesting known associations between PML NBs and other nuclear compartments, and comment upon their implications for PML NB function.
Batty E, Jensen K, Freemont P, 2009, PML nuclear bodies and their spatial relationships in the mammalian cell nucleus, FRONTIERS IN BIOSCIENCE-LANDMARK, Vol: 14, Pages: 1182-U7, ISSN: 2768-6701
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- Citations: 16
Briggs LC, Baldwin GS, Miyata N, et al., 2008, Analysis of nucleotide binding to p97 reveals the properties of a tandem AAA hexameric ATPase, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 283, Pages: 13745-13752
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- Citations: 64
Yeung HO, Kloppsteck P, Niwa H, et al., 2008, Insights into adaptor binding to the AAA protein p97, BIOCHEMICAL SOCIETY TRANSACTIONS, Vol: 36, Pages: 62-67, ISSN: 0300-5127
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- Citations: 107
Foerster A, Freemont PS, Mayer RJ, 2008, AAA proteins and the life process, BIOCHEMICAL SOCIETY TRANSACTIONS, Vol: 36, Pages: 59-61, ISSN: 0300-5127
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- Citations: 1
Poh J, Odendall C, Spanos A, et al., 2008, SteC is a Salmonella kinase required for SPI-2-dependent F-actin remodelling, Cellular Microbiology, Vol: 10, Pages: 20-30, ISSN: 1462-5814
Salmonella enterica serovar Typhimurium (S. Typhimurium) replicates inside mammalian cells within membrane‐bound compartments called Salmonella‐containing vacuoles. Intracellular replication is dependent on the activities of several effector proteins translocated across the vacuolar membrane by the Salmonella pathogenicity island 2 (SPI‐2)‐type III secretion system (T3SS). This is accompanied by the formation in the vicinity of bacterial vacuoles of an F‐actin meshwork, thought to be involved in maintaining the integrity of vacuolar membranes. In this study, we investigated the function of the SPI‐2 T3SS effector SteC. An steC mutant strain was not defective for intracellular replication or attenuated for virulence in mice. However, the steC mutant was defective for SPI‐2‐dependent F‐actin meshwork formation in host cells, although the vacuolar membranes surrounding mutant bacteria appeared to be normal. Expression of SteC in fibroblast cells following transfection caused extensive rearrangements of the F‐actin cytoskeleton. Sequence analysis identified amino acid similarity between SteC and the human kinase Raf‐1. A His‐tagged SteC fusion protein had kinase activity in vitro and a point mutant lacking kinase activity was unable to induce F‐actin rearrangements in vivo. We conclude that SPI‐2‐dependent F‐actin meshwork formation depends on the kinase activity of SteC, which resembles more closely eukaryotic than prokaryotic kinases.
Isaacson RL, Simpson PJ, Liu M, et al., 2007, A new labeling method for methyl transverse relaxation-optimized spectroscopy NMR spectra of alanine residues, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Vol: 129, Pages: 15428-+, ISSN: 0002-7863
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- Citations: 89
Briggs LC, Dreveny I, Pye VE, et al., 2007, p97 and Ubiquitin: A Complex Story, Protein Degradation, Pages: 149-193, ISBN: 9783527318780
p97 is an abundant, hexameric AAA ATPase, constituting 1% of the cytosol. It carries out diverse cellular roles, and is increasingly linked to ubiquitin in these processes. Ubiquitin modification determines the fate of many cellular proteins. Conjugation with a single ubiquitin molecule is a signal associated with altered protein trafficking whereas conjugation of a chain of ubiquitin can target a substrate protein to the proteasome for degradation, a function of the ubiquitin- proteasome system (UPS). Recent advances have established p97 (also known as VCP in mammals and Cdc48 in yeast) as a key part of the UPS, best characterized in the ERAD pathway. The UPS is a nonlysosomal proteolytic system, in which a candidate protein (short-lived or misfolded) is identified, modified with a ubiquitin chain, escorted to the proteasome and then unfolded, deubiquitinated and subjected to proteolysis. This involves recognition of the substrate protein and the actions of a succession of proteins on it. p97 is of particular importance as it is able to interact with many different proteins in this series of events. Current evidence points to a role for p97 in the identification and possible subsequent partial unfolding or disassembly of a given protein or protein complex. In the UPS, for example, this could be the disassembly of ubiquitinated proteins from unmodified proteins, prior to capture by the following interacting protein. It appears that this functionality possibly extends to other cellular processes that p97 participates in, such as post-mitotic membrane fusion. In this chapter we will give an overview of these p97 interacting proteins and detail how p97 targets ubiquitin-modified proteins in cellular processes such as ERAD. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA.
Briggs LC, Dreveny I, Pye VE, et al., 2007, p97 and Ubiquitin: A Complex Story, Protein Degradation: Cell Biology of the Ubiquitin-Proteasome System, Pages: 149-193, ISBN: 9783527314355
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- Citations: 1
Martin CA, Longman E, Wooding C, et al., 2007, Cd36, a class B scavenger receptor, functions as a monomer to bind acetylated and oxidized low-density lipoproteins, PROTEIN SCIENCE, Vol: 16, Pages: 2531-2541, ISSN: 0961-8368
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- Citations: 21
Kitney RI, Freemont PS, Rouilly V, 2007, Engineering a molecular predation oscillator, IET Synthetic Biology, Vol: 1, Pages: 68-70, ISSN: 1752-1394
The paper addresses the problem of designing and building a stable molecular based oscillator which can be controlled in terms of both amplitude and frequency. A study of previous oscillators of this type showed that they are inherently unstable. To overcome this problem a design was chosen which is based on Lotka-Voltera dynamics. An important aspect of the work was the use of what we term the Engineering Cycle; that is, the cycle of system specification, design, modelling, implementation, and testing and validation. The Lotka-Voltera dynamic, in the context of a predation oscillator, amounts to a predator-prey approach. This is the basis of the oscillator design. The oscillator was designed and detailed modelling undertaken to establish the modes of the dynamic; how it could be tuned for stability; and how to control its amplitude and frequency. The biological implementation of the design was undertaken using a number of BioBricks from the MIT registry (http://parts.mit.edu/registry/ index.php/Main_Page), together with a number of parts which we designed and built. © 2007 The Institution of Engineering and Technology.
Shiels C, Adams NM, Islam SA, et al., 2007, Quantitative analysis of cell nucleus organisation, Plos Computational Biology, Vol: 3, Pages: 1161-1168, ISSN: 1553-7358
There are almost 1,300 entries for higher eukaryotes in the Nuclear Protein Database. The proteins' subcellular distribution patterns within interphase nuclei can be complex, ranging from diffuse to punctate or microspeckled, yet they all work together in a coordinated and controlled manner within the three-dimensional confines of the nuclear volume. In this review we describe recent advances in the use of quantitative methods to understand nuclear spatial organisation and discuss some of the practical applications resulting from this work.
Isaacson RL, Pye VE, Simpson P, et al., 2007, Detailed structural insights into the p97-Npl4-Ufd1 interface, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 282, Pages: 21361-21369
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- Citations: 55
Barrett A, Santangelo S, Tan K, et al., 2007, Breast cancer associated transcriptional repressor PLU-1/JARID1B interacts directly with histone deacetylases, INTERNATIONAL JOURNAL OF CANCER, Vol: 121, Pages: 265-275, ISSN: 0020-7136
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- Citations: 75
Carpenter EP, Corbett A, Thomson H, et al., 2007, AP endonuclease paralogues with distinct activities in DNA repair and bacterial pathogenesis, EMBO JOURNAL, Vol: 26, Pages: 1363-1372, ISSN: 0261-4189
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- Citations: 39
Rytkonen A, Poh J, Garmendia J, et al., 2007, SseL, a <i>Salmonella</i> deubiquitinase required for macrophage killing and virulence, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 104, Pages: 3502-3507, ISSN: 0027-8424
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- Citations: 179
Muzzolini L, Beuron F, Patwardhan A, et al., 2007, Different quaternary structures of human RECQ1 are associated with its dual enzymatic activity, PLoS Biology, Vol: 5, Pages: 157-168, ISSN: 1544-9173
RecQ helicases are essential for the maintenance of chromosome stability. In addition to DNA unwinding, some RecQ enzymes have an intrinsic DNA strand annealing activity. The function of this dual enzymatic activity and the mechanism that regulates it is, however, unknown. Here, we describe two quaternary forms of the human RECQ1 helicase, higher-order oligomers consistent with pentamers or hexamers, and smaller oligomers consistent with monomers or dimers. Size exclusion chromatography and transmission electron microscopy show that the equilibrium between the two assembly states is affected by single-stranded DNA (ssDNA) and ATP binding, where ATP or ATPγS favors the smaller oligomeric form. Our three-dimensional electron microscopy reconstructions of human RECQ1 reveal a complex cage-like structure of approximately 120 Å × 130 Å with a central pore. This oligomeric structure is stabilized under conditions in which RECQ1 is proficient in strand annealing. In contrast, competition experiments with the ATPase-deficient K119R and E220Q mutants indicate that RECQ1 monomers, or tight binding dimers, are required for DNA unwinding. Collectively, our findings suggest that higher-order oligomers are associated with DNA strand annealing, and lower-order oligomers with DNA unwinding.
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