• PtdIns5P is an oxidative stress-induced second messenger that regulates PKB activation.

      Jones, David R; Foulger, Rebecca; Keune, Willem-Jan; Bultsma, Yvette; Divecha, Nullin; Cancer Research UK Inositide Laboratory, The Paterson Institute for Cancer Research, University of Manchester, Manchester UK. (2012-12-14)
      Oxidative stress initiates signaling pathways, which protect from stress-induced cellular damage, initiate apoptosis, or drive cells into senescence or into tumorigenesis. Oxidative stress regulates the activity of the cell survival factor PKB, through the regulation of PtdIns(3,4,5)P(3) synthesis. Whether oxidative stress regulates other phosphoinositides to control PKB activation is not clear. Here we show that PtdIns5P is a redox-regulated second messenger. In response to hydrogen peroxide (H(2)O(2)), we measured an increase in PtdIns5P in cells derived from human osteosarcoma, U2OS (5-fold); breast tumors, MDA-MB-468 (2-fold); and fibrosarcoma, HT1080 (3-fold); and in p53-null murine embryonic fibroblasts (8-fold). In U2OS cells, the increase in H(2)O(2)-dependent PtdIns5P did not require mTOR, PDK1, PKB, ERK, and p38 signaling or PIKfyve, a lipid kinase that increases PtdIns5P in response to osmotic and oncogenic signaling. A reduction in H(2)O(2)-induced PtdIns5P levels by the overexpression of PIP4K revealed its role in PKB activation. Suppression of H(2)O(2)-induced PtdIns5P generation reduced PKB activation and, surprisingly, reduced cell sensitivity to growth inhibition by H(2)O(2). These data suggest that inhibition of PIP4K signaling might be useful as a novel strategy to increase the susceptibility of tumor cells to therapeutics that function through increased oxidative stress.-Jones, D. R., Foulger, R., Keune, W.-J., Bultsma, Y., Divecha, N. PtdIns5P is an oxidative stress-induced second messenger that regulates PKB activation.
    • PTPsigma promotes retinal neurite outgrowth non-cell-autonomously.

      Sajnani, Gustavo; Aricescu, A Radu; Jones, E Yvonne; Gallagher, John T; Alete, Daniel; Stoker, Andrew; Neural Development Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK. (2005-10)
      The receptor-like protein tyrosine phosphatase (RPTP) PTPsigma controls the growth and targeting of retinal axons, both in culture and in ovo. Although the principal actions of PTPsigma have been thought to be cell-autonomous, the possibility that RPTPs related to PTPsigma also have non-cell-autonomous signaling functions during axon development has also been supported genetically. Here we report that a cell culture substrate made from purified PTPsigma ectodomains supports retinal neurite outgrowth in cell culture. We show that a receptor for PTPsigma must exist on retinal axons and that binding of PTPsigma to this receptor does not require the known, heparin binding properties of PTPsigma. The neurite-promoting potential of PTPsigma ectodomains requires a basic amino acid domain, previously demonstrated in vitro as being necessary for ligand binding by PTPsigma. Furthermore, we demonstrate that heparin and oligosaccharide derivatives as short as 8mers, can specifically block neurite outgrowth on the PTPsigma substrate, by competing for binding to this same domain. This is the first direct evidence of a non-cell-autonomous, neurite-promoting function of PTPsigma and of a potential role for heparin-related oligosaccharides in modulating neurite promotion by an RPTP.
    • Publisher Correction: Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK 'Alert Level 4' phase of the B-MaP-C study

      Dave, R. V.; Kim, B.; Courtney, A.; O'Connell, R.; Rattay, T.; Taxiarchi, V. P.; Kirkham, J. J.; Camacho, E. M.; Fairbrother, P.; Sharma, N.; et al. (2021)
    • Publisher correction: genomic instability in mutant p53 cancer cells upon entotic engulfment.

      Mackay, H; Moore, D; Hall, Callum; Birkbak, N; Jamal-Hanjani, M; Karim, S; Phatak, V; Piñon, L; Morton, J; Swanton, C; et al. (2018-08-28)
      The original version of this article incorrectly omitted an affiliation of Patricia A. J. Muller: 'Cancer Research UK Manchester Institute, The University of Manchester | Alderley Park, Manchester, SK10 4TG, UK'. This has been corrected in both the PDF and HTML versions of the Article.
    • Publisher Correction: In silico prediction of housekeeping long intergenic non-coding RNAs reveals HKlincR1 as an essential player in lung cancer cell survival

      Memon, Danish; Bi, J; Miller, Crispin J; RNA Biology Group, CRUK Manchester Institute, The University of Manchester, Alderley Park, Manchester, SK10 4TG, (2019)
    • Publisher correction: Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways.

      Duffy, DL; Zhu, G; Li, X; Sanna, M; Iles, MM; Jacobs, LC; Evans, DM; Yazar, S; Beesley, J; Law, MH; et al. (2019)
      The original version of this Article contained errors in the spelling of the authors Fan Liu and M. Arfan Ikram, which were incorrectly given as Fan Lui and Arfan M. Ikram. In addition, the original version of this Article also contained errors in the author affiliations which are detailed in the associated Publisher Correction.
    • Publisher correction: ultraviolet radiation-induced DNA damage is prognostic for outcome in melanoma

      Trucco, Lucas D; Mundra, Piyushkumar A; Hogan, Kate; Garcia-Martinez, Pablo; Viros, Amaya; Mandal, Amit Kumar; Macagno, N; Gaudy-Marqueste, C; Allan, D; Baenke, Franziska; et al. (2018)
      In the version of this article originally published, Extended Data Fig. 3 was incorrect. A duplicate of Extended Data Fig. 4 was uploaded in place of Extended Data Fig. 3. Extended Data Fig. 3 has now been uploaded. The error has been fixed in the PDF and HTML versions of this article.
    • Pulse irradiation of aqueous solutions containing ferrous and chloride ions: Reaction between Cl2- and HO2.

      Gilbert, C W; Ingalls R B; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (1977)
    • Pulse radiolysis and cellular studies of a new class of radiosensitizers: 2-nitrobenzofurans.

      Averbeck, D; Bensasson, R V; Buisson, J; Land, Edward J; Rene, L; Royer, R; Santus, R; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Withington, Manchester, M20 9BX, UK (1982-10)
      A group of 2-nitrobenzofurans possessing antibacterial and antiparasitic properties have now been shown to be potential radiosensitizers from investigations in simple aqueous solution by pulse radiolysis and from survival studies in yeast. The radical anions of several 2-nitrobenzofurans were formed by the rapid reaction of the parent molecules with hydrated electrons or with various pyrimidine electron adducts. Studies of equilibria between these radical anions, the parent nitrobenzofurans and the corresponding species derived from quinones with known one-electron reduction potentials, showed that the one-electron reduction potentials of all the furans under investigation lie between -285 and -309 mV. They are thus more electron affinic than the nitroimidazoles (misonidazole and metronidazole) currently under clinical evaluation. 5-Hydroxy- and 7-hydroxy-2-nitrobenzofuran were demonstrated to form weak complexes with DNA (binding constant 80 M-1) and strong complexes with HSA (binding constant 10(5)M-1). In the yeast Saccharomyces cerevisiae the nitrobenzofurans exert radiosensitizing effects on survival either similar to or higher than misonidazole.
    • Pulse radiolysis and flash photolysis: some applications in biology and medicine.

      Land, Edward J; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester, M20 9BX, England. (1980)
    • A pulse radiolysis investigation of the oxidation of methoxylated metabolites of indolic melanin precursors.

      Lambert, Christopher R; Land, Edward J; Riley, P A; Truscott, T G; Paterson Institute for Cancer Research, Christie Hospital and Holt Radium Institute, Manchester, U.K. (1990-09-14)
      The rate constants associated with the series of successive transient absorptions initiated by one-electron oxidation of 6-hydroxy-5-methoxyindole (6H5MI) and its isomer 5-hydroxy-6-methoxyindole (5H6MI) have been studied by pulse radiolysis. These close analogues of 5,6-dihydroxyindole (DHI) are metabolites of the oxidative melanogenic pathway. The species initially produced from N3. oxidation of both methoxyindoles at pH 7.2-7.4 are assigned as the corresponding semiquinones. That from 6H5MI shows peak at 500, 370 and 330 nm, very close to those of the semiquinone of DHI, whereas the semiquinone of 5H6MI shows no absorption at 500 nm but bands at 420 and 340 nm. These spectral differences are attributed to marked changes in the degrees of electron delocalisation for the two types of radical, both rings of the indole being involved for the 6H5MI radical but only the benzenoid moiety for the 5H6MI radical. In both cases, the radicals decayed, probably by disproportionation, into products which absorbed in the 400-420 nm region. For 6H5MI, the subsequent decay in this region was best fitted by two consecutive first-order processes which were both strongly base-catalysed. The first of these processes is assigned to partial decay via deprotonation of the corresponding quinonoid cation to form an equilibrium mixture of this cation and the corresponding quinone methide. The second process is assigned to reaction of the quinone methide with water yielding hydroxylated product(s) which may subsequently react with remaining quinonoid cation or quinone methide to give dimeric product(s) with broad absorption centreing in the 550 nm region detected 0.5 s after the pulse. For 5H6MI, the decay at 430 nm fitted a single first-order process, which was weakly base-catalysed. This process is attributed to deprotonation of the corresponding quinonoid cation to the corresponding quinone imine absorbing below 350 nm, which was stable for at least tens of seconds. The current experiments suggest that our previous analogues observations (Lambert et al. (1989) Biochim. Biophys. Acta 993, 12-20) on the oxidation of the melanogenic precursors DHI and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) may be interpreted, as with 6H5MI, in terms of the corresponding indolequinones decaying into equilibrium mixtures of quinone, quinone imine and quinone methide. These decay via reaction of the methide with water generating hydroxylated species which proceed to give the coloured product(s) absorbing in the 550 nm region.
    • A pulse radiolysis investigation of the oxidation of the melanin precursors 3,4-dihydroxyphenylalanine (dop) and the cysteinyldopas

      Thompson, A; Land, Edward J; Chedekel, M; Subbarao, K; Truscott, T G; Department of Chemistry, Paisley College, Paisley, PA1 2BE (2010-12-07)
    • Pulse radiolysis studies of ortho-quinone chemistry relevant to melanogenesis.

      Land, Edward J; Ramsden, Christopher A; Riley, Patrick A; CRC Drug Development Group, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, UK. eland@mighty-micro.co.uk (2001-11-15)
      The contributions of pulse radiolysis towards characterisation of unstable ortho-quinones relevant to melanogenesis are reviewed. The quinones discussed include dopaquinone, the precursor of both eumelanogenesis and phaeomelanogenesis, and 5-S-cysteinyldopaquinone, an early component of the phaeomelanogenic pathway. Redox exchange between dopaquinone and 5-S-cysteinyldopa is shown to be a determinant of the balance between eumelanogenesis and phaeomelanogenesis. Ortho-quinones resulting from the oxidation of tertiary N,N-dialkylcatecholamines cyclise to redox-inactive betaines which fail to autoactivate tyrosinase. This is consistent with the dopa detected during melanogenesis catalysed by tyrosinase being formed indirectly by a combination of dopaquinone intramolecular reductive addition to form leucodopachrome (cyclodopa), followed by redox exchange between remaining dopaquinone and leucodopachrome. Rapid tautomerism of the ortho-quinone of 4-cyanomethylcatechol to a redox-inactive quinomethane likewise inhibits tyrosinase autoactivation. The incorporation of trihydric phenol moieties in melanin is modelled by the reactions of several ortho-quinones with phloroglucinol, which itself is not directly oxidised by tyrosinase due to the meta-positioning of the hydroxyl groups. The importance of a susceptibility towards nucleophilic attack as well as a propensity to undergo redox-exchange, in the chemistry of melanogenic ortho-quinones, is emphasised.
    • Pulse radiolysis study of buckminsterfullerene in benzene solution. Assignment of the C60 triplet-triplet absorption spectrum

      Bensasson, R V; Hill, T; Land, Edward J; Leach, S; Truscott, T G; Laboratoire de Biophysique, Museum National d'Histoire Naturelle, INSERM U201, 43 rue Cuvier, 75231 Paris Cedex 05, France (1993)
    • Pulse radiolysis study of chlorpromazine and promazine free radicals in aqueous solution.

      Davies, A; Land, Edward J; Navaratnam, S; Parsons, B; Phillips, G (1979)
    • Pulse radiolysis study of protoferrihaem IX intercalated in sodium dodecyl sulphate micelles.

      Evers, E L; Jayson, G G; Swallow, A John; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (1978)
    • A pulse radiolysis study of the complexing of furocoumarins with DNA and proteins.

      Beaumont, P C; Land, Edward J; Navaratnam, S; Parsons, B J; Phillips, G O; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester, M20 9BX, England (1980-06-27)
      The complexing of furocoumarins with DNA in aqueous solution has been investigated using the fast-reaction technique of pulse radiolysis. Association constants are given for 8-methoxypsoralen, psoralen, khellin, angelicin, 5,7-dimethoxycoumarin, 5-methoxypsoralen and 4'-aminomethyl-4,5',8-trimethylpsoralen. In addition, the complexing of some furocoumarins to the protein, bovine serum albumin, has also been studied.
    • Pulse radiolytic and electrochemical investigations of intramolecular electron transfer in carotenoporphyrins and carotenoporphyrin-quinone triads

      Land, Edward J; Lexa, D; Bensasson, R V; Gust, D; Moore, T A; Moore, A L; Liddell, P A; Nemeth, G A; Paterson Institute for Cancer Research, CHristie Hospital and Holt Radium Institute, Manchester M20 9BX, U.K. (1987)
    • Pulse-radiolysis study of a biological matrix.

      Cercek, B; Cercek, L; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (1973-08)
    • Pulse-radiolysis study of the effect of pH on the one-electron reduction potentials of lumichrome derivatives

      Heelis, P; Parsons, B; Phillips, G; Land, Edward J; Swallow, A John; Research Division, North East Wales Institute, Deeside, Clwyd CH5 4BR (1985)