Showing papers by "University of Dundee published in 1995"
TL;DR: It is shown that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3, and it is demonstrated that PKB is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC).
Abstract: Glycogen synthase kinase-3 (GSK3) is implicated in the regulation of several physiological processes, including the control of glycogen and protein synthesis by insulin, modulation of the transcription factors AP-1 and CREB, the specification of cell fate in Drosophila and dorsoventral patterning in Xenopus embryos. GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k). Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase.
5,158 citations
TL;DR: The biochemical functions of GST are described to show how individual isoenzymes contribute to resistance to carcinogens, antitumor drugs, environmental pollutants, and products of oxidative stress, and to allow identification of factors that may modulate resistance to specific noxious chemicals.
Abstract: The glutathione S-transferases (GST) represent a major group of detoxification enzymes. All eukaryotic species possess multiple cytosolic and membrane-bound GST isoenzymes, each of which displays distinct catalytic as well as noncatalytic binding properties: the cytosolic enzymes are encoded by at least five distantly related gene families (designated class alpha, mu, pi, sigma, and theta GST), whereas the membrane-bound enzymes, microsomal GST and leukotriene C, synthetase, are encoded by single genes and both have arisen separately from the soluble GST. Evidence suggests that the level of expression of GST is a crucial factor in determining the sensitivity of cells to a broad spectrum of toxic chemicals. In this article the biochemical functions of GST are described to show how individual isoenzymes contribute to resistance to carcinogens, antitumor drugs, environmental pollutants, and products of oxidative stress.A description of the mechanisms of transcriptional and posttranscriptional regulat...
3,516 citations
TL;DR: The results indicate that the activation of Raf is suppressed and that its inactivation is accelerated by a downstream component(s) of the MAP kinase pathway.
3,444 citations
TL;DR: In this paper, a review of the corporate social reporting literature, its major theoretical preoccupations and empirical conclusions, attempts to re-examine the theoretical tensions that exist between “classical” political economy interpretations of social disclosure and those from more “bourgeois” perspectives.
Abstract: Takes as its departure point the criticism of Guthrie and Parker by Arnold and the Tinker et al. critique of Gray et al. Following an extensive review of the corporate social reporting literature, its major theoretical preoccupations and empirical conclusions, attempts to re‐examine the theoretical tensions that exist between “classical” political economy interpretations of social disclosure and those from more “bourgeois” perspectives. Argues that political economy, legitimacy theory and stakeholder theory need not be competitor theories but may, if analysed appropriately, be seen as alternative and mutually enriching theories from alternative levels of resolution. Offers evidence from 13 years of social disclosure by UK companies and attempts to interpret this from different levels of resolution. There is little doubt that social disclosure practice has changed dramatically in the period. The theoretical perspectives prove to offer different, but mutually enhancing, interpretations of these phenomena.
2,923 citations
TL;DR: It is established that MAPKAP kinase‐2 is a physiological RK substrate, and that HSP27 is phosphorylated by MAPK AP kinase-2 in vivo.
2,097 citations
TL;DR: In this article, an attempt to build a database of UK company social and environmental disclosure is described, with the aim of providing, first, a data set which both refines and develops earlier attempts to capture and interpret such disclosures; second, a dataset covering several years to permit longitudinal analysis; and third, a public database for accounting researchers who wish to pursue, in a systematic and comparable way, more focused hypotheses about social and Environmental reporting behaviour.
Abstract: Responds to the widely‐reported methodological problems which have arisen in research into corporate social and environmental reporting. Reports on an attempt to build a database of UK company social and environmental disclosure. The motivation behind the database is an attempt to provide, first, a data set which both refines and develops earlier attempts to capture and interpret such disclosures; second, a data set covering several years to permit longitudinal analysis; and third, a public database for accounting researchers who wish to pursue, in a systematic and comparable way, more focused hypotheses about social and environmental reporting behaviour. Explains the motivation for, the background to, and process of establishing such a database and attempts to expose the difficulties met and the assumptions made in establishing the structure of the data capture. The resultant database has already proved useful to other UK researchers. Aims to help researchers in other countries to develop their own metho...
1,191 citations
TL;DR: AICAR provides direct evidence that the inhibition by AMPK of activation of hormone-sensitive lipase by cyclic-AMP-dependent protein kinase also operates in intact cells, and should be a useful tool for identifying new target pathways and processes regulated by theprotein kinase cascade.
Abstract: The AMP-activated protein kinase (AMPK) is believed to protect cells against environmental stress (e.g. heat shock) by switching off biosynthetic pathways, the key signal being elevation of AMP. Identification of novel targets for the kinase cascade would be facilitated by development of a specific agent for activating the kinase in intact cells. Incubation of rat hepatocytes with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) results in accumulation of the monophosphorylated derivative (5-aminoimidazole-4-carboxamide ribonucleoside; ZMP) within the cell. ZMP mimics both activating effects of AMP on AMPK, i.e. direct allosteric activation and promotion of phosphorylation by AMPK kinase. Unlike existing methods for activating AMPK in intact cells (e.g. fructose, heat shock), AICAR does not perturb the cellular contents of ATP, ADP or AMP. Incubation of hepatocytes with AICAR activates AMPK due to increased phosphorylation, causes phosphorylation and inactivation of a known target for AMPK (3-hydroxy-3-methylglutaryl-CoA reductase), and almost total cessation of two of the known target pathways, i.e. fatty acid and sterol synthesis. Incubation of isolated adipocytes with AICAR antagonizes isoprenaline-induced lipolysis. This provides direct evidence that the inhibition by AMPK of activation of hormone-sensitive lipase by cyclic-AMP-dependent protein kinase, previously demonstrated in cell-free assays, also operates in intact cells. AICAR should be a useful tool for identifying new target pathways and processes regulated by the protein kinase cascade.
1,185 citations
TL;DR: AICAR provides direct evidence that the inhibition by AMPK of activation of hormone-sensitive lipase by cyclic-AMP-dependent protein kinase also operates in intact cells, and should be a useful tool for identifying new target pathways and processes regulated by theprotein kinase cascade.
Abstract: The AMP-activated protein kinase (AMPK) is believed to protect cells against environmental stress (e.g. heat shock) by switching off biosynthetic pathways, the key signal being elevation of AMP. Identification of novel targets for the kinase cascade would be facilitated by development of a specific agent for activating the kinase in intact cells. Incubation of rat hepatocytes with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) results in accumulation of the monophosphorylated derivative (5-aminoimidaz-ole-4-carboxamide ribonucleoside; ZMP) within the cell. ZMP mimics both activating effects of AMP on AMPK, i.e. direct allosteric activation and promotion of phosphorylation by AMPK kinase. Unlike existing methods for activating AMPK in intact cells (e.g. fructose, heat shock), AICAR does not perturb the cellular contents of ATP, ADP or AMP. Incubation of hepatocytes with AICAR activates AMPK due to increased phosphorylation, causes phosphorylation and inactivation of a known target for AMPK (3-hydroxy-3-methylglutaryl-CoA reductase), and almost total cessation of two of the known target pathways, i.e. fatty acid and sterol synthesis. Incubation of isolated adipocytes with AICAR antagonizes isoprenaline-induced lipolysis. This provides direct evidence that the inhibition by AMPK of activation of hormone-sensitive lipase by cyclic-AMP-dependent protein kinase, previously demonstrated in cell-free assays, also operates in intact cells. AICAR should be a useful tool for identifying new target pathways and processes regulated by the protein kinase cascade.
871 citations
TL;DR: The size of the single centrosomal body in these circular figures suggests that loss of function of the serine-threonine protein kinase encoded by aur leads to a failure of the centrosomes to separate and form a bipolar spindle.
830 citations
TL;DR: Recent advances in this field are reviewed and the therapeutic potential of this novel, non-genomic effect of steroids is discussed and whether they may influence behaviour under physiological, or pathophysiological, conditions is investigated.
725 citations
TL;DR: It is shown that AMPK activates the AMPK cascade by four mechanisms, which should make the system exquisitely sensitive to changes in AMP concentration.
TL;DR: The development of a highly specific peptide activation system that is consistent with an allosteric mechanism of negative regulation of p53 tetramer activity and that forms a precedent for the synthesis of novel low molecular mass modifiers of the p53 response is presented.
TL;DR: The results suggest that CaMKIK and AMPKK are distinct enzymes dedicated to their respective kinase targets but with some overlap in their substrate specificities.
TL;DR: Brefeldin et al. as mentioned in this paper provided morphological evidence that proteins taken up by macropinocytosis can gain access to the cytosol and therefore into the conventional class I MHC pathway.
TL;DR: The structure of PP1 provides insight into the molecular mechanism for substrate recognition, enzyme regulation and inhibition of this enzyme by toxins and tumour promoters and a basis for understanding the expanding family of related phosphatases which include PP2A and PP2B (calcineurin).
TL;DR: A Schizosaccharomyces pombe gene with homology to the budding yeast gene CDC5, the Drosophila gene polo, and the mammalian family of genes encoding polo-like kinases is identified and disruption of this gene, plo1+, indicates that it is essential.
Abstract: We have identified a Schizosaccharomyces pombe gene with homology to the budding yeast gene CDC5, the Drosophila gene polo, and the mammalian family of genes encoding polo-like kinases. Disruption of this gene, plo1+, indicates that it is essential. Loss of plo1+ function leads to a mitotic arrest in which condensed chromosomes are associated with a monopolar spindle or to the failure of septation following the completion of nuclear division. In the latter case, cells show a failure both in the formation of an F-actin ring and in the deposition of septal material, suggesting that plo1+ function is required high in the regulatory cascade that controls septation. The overexpression of plo1+ in wild-type cells also results in the formation of monopolar spindles but also induces the formation of multiple septa without nuclear division. Septation can also be induced in the absence of mitotic commitment and concomitant spindle formation by the overexpression of plo1+ in cdc25-22 or cdc2-33 cells arrested in G2; in G1 cells arrested at Start by the cdc10-V50 mutation, or in cells lacking the cyclin B homolog cdc13 that undergo repeated S phases in the absence of mitosis.
TL;DR: The glutathione S-transferase (GST) supergene family comprises gene families that encode isoenzymes that are widely expressed in mammalian tissue cytosols and membranes that play a pivotal role in protecting cells from the consequences of oxidative stress.
Abstract: The glutathione S-transferase (GST) supergene family comprises gene families that encode isoenzymes that are widely expressed in mammalian tissue cytosols and membranes. Both cytosolic (particularly the isoenzymes encoded by the alpha, mu and theta gene families) and microsomal GST catalyse the conjugation of reduced glutathione (GSH) with a wide variety of electrophiles which include known carcinogens as well as various compounds that are products of oxidative stress including oxidised DNA and lipid. Indeed, several lines of evidence suggest certain of these isoenzymes play a pivotal role in protecting cells from the consequences of such stress. An assessment of the importance of these GST in humans is presently difficult however, because the number of alpha and theta class genes is not known and, the catalytic preferences of even identified isoforms is not always clear.
TL;DR: The rapid inactivation of p42mapk initiated five minutes after stimulation of endothelial, adipose and chromaffin cells with growth factor, and was initiated by the major vanadate-sensitive Tyr 185-specific phosphatase, explaining why dephosphorylation of Thr 183 is rate-limiting for p42 mapk inactivation in PC12 cells after stimulation with EGF.
TL;DR: Understanding of the occurrence of the toxins in aquatic environments and their actions at the molecular level and with whole organisms in laboratory studies indicates that this is possible.
TL;DR: This work has analysed phosphorylation of the synthetic peptide AMARAASAAALARRR, and 23 variants, by mammalian, higher plant and yeast members of the SNF1 protein kinase subfamily, and by mammalian calmodulin‐dependentprotein kinase I (CaMKI).
TL;DR: The results indicate that the measurement of these compounds in plasma is a valid indicator of NO generation in fasted human volunteers and thus defines the quantitative relationship between the L-arginine:nitric oxide (NO) pathway and the formation of these oxides of nitrogen.
TL;DR: It is shown that Jadassohn–Lewandowsky PC is caused by a heterozygous missense mutation in the helix initiation peptide of K16 (Leu130Pro), and the known expression patterns of these keratins in epidermal structures correlates with the specific abnormalities observed in each form of PC.
Abstract: Pachyonychia congenita (PC) is a group of autosomal dominant disorders characterized by dystrophic nails and other ectodermal aberrations A gene for Jackson–Lawler PC was recently mapped to the type I keratin cluster on 17q Here, we show that a heterozygous missense mutation in the helix initiation motif of K17 (Asn92Asp) co–segregates with the disease in this kindred We also show that Jadassohn–Lewandowsky PC is caused by a heterozygous missense mutation in the helix initiation peptide of K16 (Leu130Pro) The known expression patterns of these keratins in epidermal structures correlates with the specific abnormalities observed in each form of PC
TL;DR: Current interest focuses on developing novel cancer therapies based on the knowledge of the activity of p53 and p21Cip1 in the cell cycle.
Abstract: The human tumour suppressor protein p53 is critical for regulation of the cell cycle on genotoxic insult. When DNA is damaged by radiation, chemicals or viral infection, cells respond rapidly by arresting the cell cycle. A G1 arrest requires the activity of wild-type p53, as it is not observed in cells lacking functionally wild-type protein, and at least some component of S phase and G2/M arrests is also thought to be p53-dependent. p53 functions as a transcription factor which binds specific DNA sequences, and recently major downstream targets have been identified, including p21Cip1, an inhibitor of the cell cycle kinases that also blocks the replicative but not the repair function of DNA polymerase delta auxiliary factor, PCNA. Current interest focuses on developing novel cancer therapies based on our knowledge of the activity of p53 and p21Cip1 in the cell cycle.
TL;DR: In this article, the authors argue that the numerous and ad hoc conceptualizations undermine the concept of the marketing mix and propose that Booms and Bitner's (1981) 7Ps mix for services be extended to other areas of marketing.
Abstract: McCarthy′s 4Ps mix has increasingly come under attack with the result that different marketing mixes have been put forward for different marketing contexts. Contends that the numerous and ad hoc conceptualizations undermine the concept of the marketing mix and proposes that Booms and Bitner′s (1981) 7Ps mix for services be extended to other areas of marketing. Shows how the 7Ps framework can be applied to consumer goods and reports the results of a survey of UK and European marketing academics which suggest that there is a high degree of dissatisfaction with 4Ps. Also suggests that the 7Ps framework has already achieved a high degree of acceptance as a generic marketing mix among both groups of respondents. Overall provides fairly strong support for the view that Booms and Bitner′s 7Ps framework should replace McCarthy′s 4Ps framework.
TL;DR: The development of minimal access surgery has raised issues that extend beyond the technical aspects of operative patient care and has given prominence to economic concerns that transcend the ongoing debate concerning the relative cost benefit of the new surgical approach versus conventional open surgery.
Abstract: I n years to come, the advent of laparoscopic cholecystectomy (LC) will be seen as a significant milestone in the history of surgery. Indeed, it is a momentous advance which has already had a momentous impact. Nonetheless, the early post-LC years witnessed an uncontrolled expansion of surgical endoscopic practice, at times not far short of abuse, which amounted to the biggest unaudited freefor-all in the history of surgery. The leaders of our profession lacked the foresight to grasp the implications of Wittmoser and Semm’s pioneering work in laparoscopic and thoracoscopic techniques,‘.2 and the majority of established surgical training departments were totally unprepared to deal with them. By default. then, the unprecedented expansion of minimal access surgery (MAS) was largely a peripheral phenomenon. Now that the dust has settled. it is important to analyze how MAS has altered surgical practice and training and how it will continue to do so in the future. The development of MAS has raised issues that extend beyond the technical aspects of operative patient care. First, it has given prominence to economic concerns that transcend the ongoing debate concerning the relative cost benefit of the new surgical approach versus conventional open surgery. Studies of cost efficacy, utility, and benefit, using objective parameters such as quality-of-life-adjusted years (QALYs), will assume increasing importance as future developments impose extra burdens on limited resources. Regrettably, in the economic area too, the reports on MAS have lacked scientific objectivity, producing wildly different conclusions on the basis of data that are often suspect. One major indirect benefit of MAS has been to emphasize. as never before, the importance of minimizing the trauma of surgical operative treatment-the raison d’&tre of endoscopic surgery.
TL;DR: PCNA and the cell-cycle regulator p21WAF1 interact in vivo, and it is shown that this interaction requires the central loop of PCNA and an eight amino-acid motif from the carboxyl terminus of p21 WAF1.
TL;DR: It is demonstrated that bound antibodies can modulate the capture of peptides by class II major histocompatibility complex (MHC), thus manipulating the T cell response towards or away from particular determinants.
Abstract: Bound antibodies can modulate antigen processing but it is not clear to what extent this affects antigen presentation. Here we show that presentation of T cell determinants in tetanus toxin can be either enhanced or suppressed as a direct consequence of antibody modulation of antigen processing in human B lymphoblastoid cells. Remarkably, a single bound antibody or its Fab fragment can simultaneously enhance the presentation of one T cell determinant by more than 10-fold while strongly suppressing the presentation of a different T cell determinant. Biochemical analysis demonstrates that both the suppressed and boosted determinants fall within an extended domain of antigen stabilized or "footprinted" by this antibody during proteolysis. These results demonstrate that bound antibodies can modulate the capture of peptides by class II major histocompatibility complex (MHC), thus manipulating the T cell response towards or away from particular determinants. Altered processing of protein-protein complexes leading to enhanced loading of class II MHC and substantially lowered threshold for T cell activation suggests a novel mechanism that might reveal "cryptic" self determinants.
TL;DR: The identification and characterization of a protein kinase that phosphorylates mouse p53 at a single site, serine 34, a major site of phosphorylation in the cell are described, suggesting that this p53 kinase is likely to be activated by phosphorylated and may be a member of the stress-activatedprotein kinase subfamily of MAP kinases.
TL;DR: In this paper, it is argued that the learning organization is badly flawed because of its proponents' apolitical assumptions, which leads them to neglect the political activity likely to be encountered in a learning organization, activity which will tend to frustrate the learning aims.
Abstract: Three main criticisms of the 'learning organization' are developed in this paper. First, it is argued that the concept is badly flawed because of its proponents' apolitical assumptions. This leads them to neglect the political activity likely to be encountered in a learning organization, activity which will tend to frustrate the learning aims. Second, while their model allows for greater employee empowerment the amount will probably be relatively modest in real terms. On the other hand, the power of managers, especially those at the apex of the organization, is likely to be enhanced by their privileged access to any extra informational and symbolic resources that are created by individual and collective learning processes. The third, and potentially the most damning, criticism is that the concept of the 'learning organization' is expressed in ways that provide raw material for managerial ideology, potentially constraining the meanings and actions of other employees so that they support the interests of th...
TL;DR: The data suggest that the alkali-labile hydroxyester-linked fatty acids of the GPI anchor are necessary for antibody binding.