Mann, David - Imperial College London - Department of Life Sciences, Biochemistry and Biotechnology

个人简介

Dr Mann's lab is interested in cancer biology, particularly that relating to cell proliferation and signal transduction. Many cancers exhibit aberrant signal transduction and the enzymes involved can make excellent targets for therapeutic intervention. We aim to identify such targets, characterise their functions and establish techniques for regulating their activities. For more details, click the Research tab above

研究领域

Control of Mammalian Cell Proliferation At its simplistic level, cancer can be thought of as unrestrained cell division. We have a long-standing interest in the mechanisms controlling cell proliferation and how they can be misregulated in cancer. Our interests range from the molecular mechanisms underlying viral subvertion of proliferation control (Yarmishyn et al; Child & Mann) to cyclin/cyclin-dependent kinases and protein phosphorylation (Child et al; Anderson et al). We are interested in thedf links between DNA damage and cell cycle progression (Suwaki et al) and in identifying novel chemotherapeutics to block excessive proliferation, as exemplified by our collaboration with Prof Ramon Vilar to study the effects of organometal complexes as cytotoxics and/or quadruplex nucleic acid stabilizers (Suntharalingam et al). Protein Phosphorylation We are pursuing chemical genetic approaches to understand protein kinase function. Most protein kinases utilise ATP as the phosphate donor and have highly conserved catalytic sites. dThis makes many protein kinase inhibitors promiscuous in their specificity. We are using site directed mutagenesis to subtly alter the catalytic site of specific protein kinases so that they can accept analogues of ATP that are not normally used (Elphick et al). This approach allows the molecular construction of unique kinase/ATP analogue pairs and can be used for the identification of the substrates of the modified kinase (Lee et al; Elphick et al A, B). To facilitate protein kinase substrate identification wie are collaborating with Prof Ramon Vilar and Dr Joachim Steinke in the Chemistry Department at Imperial College London to develop novel matrices for specifically isolating phosphoproteins and thir derivatives. In collaboration with Prof Alan Armstrong, we are developing novel kinase inhibitors and activity-based probes to assess the functions of specific enzymes in vivo. Protein Myristoylation Protein myristoylation is the post- or co-translational modification of proteins with a C14 fatty acid (reviewed in Wright et al). This modification has been shown to be essential for thev correct functioning and/or subcellular localisation of many proteins and is important in cancer - for example, the tyrosine kinase src looses its transforming ability if it lacks N terminal myristoylation. In collaboration with Dr Ed Tate (Department of Chemistry), we are applying chemical genetic tagging to identify myristoylated proteins in mammalian cells and assess their relevance to normal and disease physiology. Novel Methods to Identify Therapeutics We are applying our molecular biological and chemical genetic expertise to develop new ways to identify targets in cancer and develop therapeutics.aWe have recently developed a new method for identifying chemical fragments that bind to a defined protein surface (Nonoo et al) and we are actively using this methodology to screen for modulators of protein-protein interactions, an under-exploited class of drug targets. In addition we have an ongoing programme developing inhibitors to the cell cycle regulatory phosphatases of the cdc25 family (Mak et al).

近期论文

查看导师新发文章（温馨提示：请注意重名现象，建议点开原文通过作者单位确认）

Thinon E, Morales-Sanfrutos J, Mann DJ, Tate EWet al., 2016, N-Myristoyltransferase Inhibition Induces ER-Stress, Cell Cycle Arrest, and Apoptosis in Cancer Cells, ACS CHEMICAL BIOLOGY, Vol: 11, Pages: 2165-2176, ISSN: 1554-8929 Stafford VS, Suntharalingam K, Shivalingam A, White AJP, Mann DJ, Vilar Ret al., 2015, Syntheses of polypyridyl metal complexes and studies of their interaction with quadruplex DNA, DALTON TRANSACTIONS, Vol: 44, Pages: 3686-3700, ISSN: 1477-9226 Tretina K, Gotia HT, Mann DJ, Silva JCet al., 2015, Theileria-transformed bovine leukocytes have cancer hallmarks, TRENDS IN PARASITOLOGY, Vol: 31, Pages: 306-314, ISSN: 1471-4922 Wang N, She Z, Lin Y-C, Martic S, Mann DJ, Kraatz H-Bet al., 2015, Clickable 5 '-gamma-Ferrocenyl Adenosine Triphosphate Bioconjugates in Kinase-Catalyzed Phosphorylations, CHEMISTRY-A EUROPEAN JOURNAL, Vol: 21, Pages: 4988-4999, ISSN: 0947-6539 Smith DE, Yong K, Mann DJ, 2014, Dysregulation of cyclin D expression in multiple myeloma alters the cell cycle response to DNA damage, 54th Annual Scientific Meeting of the British-Society-for-Haematology, Publisher: WILEY-BLACKWELL, Pages: 49-49, ISSN: 0007-1048 Thinon E, Serwa RA, Broncel M, Brannigan JA, Brassat U, Wright MH, Heal WP, Wilkinson AJ, Mann DJ, Tate EWet al., 2014, Global profiling of co- and post-translationally N-myristoylated proteomes in human cells, NATURE COMMUNICATIONS, Vol: 5, ISSN: 2041-1723 Wright MH, Clough B, Rackham MD, Rangachari K, Brannigan JA, Grainger M, Moss DK, Bottrill AR, Heal WP, Broncel M, Serwa RA, Brady D, Mann DJ, Leatherbarrow RJ, Tewari R, Wilkinson AJ, Holder AA, Tate EWet al., 2014, Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach, NATURE CHEMISTRY, Vol: 6, Pages: 112-121, ISSN: 1755-4330 Byrne SL, Yaliraki SN, Barahona M, Mann DJet al., 2013, Stability analysis of protein kinases, 9th European-Biophysical-Societies-Association Congress, Publisher: SPRINGER, Pages: S174-S174, ISSN: 0175-7571 Collins JC, Armstrong A, Chapman KL, Cordingley HC, Jaxa-Chamiec AA, Judd KE, Mann DJ, Scott KA, Tralau-Stewart CJ, Low CMRet al., 2013, Prospective use of molecular field points in ligand-based virtual screening: efficient identification of new reversible Cdc25 inhibitors, MEDCHEMCOMM, Vol: 4, Pages: 1148-1155, ISSN: 2040-2503 Eccles SA, Aboagye EO, Ali S, Anderson AS, Armes J, Berditchevski F, Blaydes JP, Brennan K, Brown NJ, Bryant HE, Bundred NJ, Burchell JM, Campbell AM, Carroll JS, Clarke RB, Coles CE, Cook GJR, Cox A, Curtin NJ, Dekker LV, Silva IDS, Duffy SW, Easton DF, Eccles DM, Edwards DR, Edwards J, Evans DG, Fenlon DF, Flanagan JM, Foster C, Gallagher WM, Garcia-Closas M, Gee JMW, Gescher AJ, Goh V, Groves AM, Harvey AJ, Harvie M, Hennessy BT, Hiscox S, Holen I, Howell SJ, Howell A, Hubbard G, Hulbert-Williams N, Hunter MS, Jasani B, Jones LJ, Key TJ, Kirwan CC, Kong A, Kunkler IH, Langdon SP, Leach MO, Mann DJ, Marshall JF, Martin LA, Martin SG, Macdougall JE, Miles DW, Miller WR, Morris JR, Moss SM, Mullan P, Natrajan R, O'Connor JPB, O'Connor R, Palmieri C, Pharoah PDP, Rakha EA, Reed E, Robinson SP, Sahai E, Saxton JM, Schmid P, Smalley MJ, Speirs V, Stein R, Stingl J, Streuli CH, Tutt ANJ, Velikova G, Walker RA, Watson CJ, Williams KJ, Young LS, Thompson AMet al., 2013, Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer, BREAST CANCER RESEARCH, Vol: 15, ISSN: 1465-542X Suntharalingam K, Mendoza O, Duarte AA, Mann DJ, Vilar Ret al., 2013, A platinum complex that binds non-covalently to DNA and induces cell death via a different mechanism than cisplatin, METALLOMICS, Vol: 5, Pages: 514-523, ISSN: 1756-5901 Yelina NE, Ziolkowski PA, Miller N, Zhao X, Kelly KA, Munoz DF, Mann DJ, Copenhaver GP, Henderson IRet al., 2013, High-throughput analysis of meiotic crossover frequency and interference via flow cytometry of fluorescent pollen in Arabidopsis thaliana, NATURE PROTOCOLS, Vol: 8, Pages: 2119-2134, ISSN: 1754-2189 Mak LH, Knott J, Scott KA, Scott C, Whyte GF, Ye Y, Mann DJ, Ces O, Stivers J, Woscholski Ret al., 2012, Arylstibonic acids are potent and isoform-selective inhibitors of Cdc25a and Cdc25b phosphatases, BIOORGANIC & MEDICINAL CHEMISTRY, Vol: 20, Pages: 4371-4376, ISSN: 0968-0896 Nonoo RH, Armstrong A, Mann DJ, 2012, Kinetic Template-Guided Tethering of Fragments, CHEMMEDCHEM, Vol: 7, Pages: 2082-2086, ISSN: 1860-7179 Ohtani N, Takahashi A, Mann DJ, Hara Eet al., 2012, Cellular senescence: a double-edged sword in the fight against cancer, EXPERIMENTAL DERMATOLOGY, Vol: 21, Pages: 1-4, ISSN: 0906-6705 Suntharalingam K, Hunt DJ, Duarte AA, White AJP, Mann DJ, Vilar Ret al., 2012, A Tri-copper(II) Complex Displaying DNA-Cleaving Properties and Antiproliferative Activity against Cancer Cells, CHEMISTRY-A EUROPEAN JOURNAL, Vol: 18, Pages: 15133-15141, ISSN: 0947-6539 Brooke GN, Culley RL, Dart DA, Mann DJ, Gaughan L, McCracken SR, Robson CN, Spencer-Dene B, Gamble SC, Powell SM, Wait R, Waxman J, Walker MM, Bevan CLet al., 2011, FUS/TLS Is a Novel Mediator of Androgen-Dependent Cell-Cycle Progression and Prostate Cancer Growth, CANCER RESEARCH, Vol: 71, Pages: 914-924, ISSN: 0008-5472 Lee SE, Elphick LM, Kramer HB, Jones AME, Child ES, Anderson AA, Bonnac L, Suwaki N, Kessler BM, Gouverneur V, Mann DJet al., 2011, The Chemoselective One-Step Alkylation and Isolation of Thiophosphorylated Cdk2 Substrates in the Presence of Native Cysteine, CHEMBIOCHEM, Vol: 12, Pages: 633-640, ISSN: 1439-4227 Anderson AA, Child ES, Prasad A, Elphick LM, Mann DJet al., 2010, Cyclin D1 and Cyclin D3 Show Divergent Responses to Distinct Mitogenic Stimulation, JOURNAL OF CELLULAR PHYSIOLOGY, Vol: 225, Pages: 638-645, ISSN: 0021-9541 Bonnac L, Lee SE, Giuffredi GT, Elphick LM, Anderson AA, Child ES, Mann DJ, Gouverneur Vet al., 2010, Synthesis and O-phosphorylation of 3,3,4,4-tetrafluoroaryl-C-nucleoside analogues, ORGANIC & BIOMOLECULAR CHEMISTRY, Vol: 8, Pages: 1445-1454, ISSN: 1477-0520