Showing papers by "University of Dundee published in 1997"
TL;DR: In this paper, a protein kinase that phosphorylates PKB α at Thr308 and increases its activity over 30-fold was found to play a key role in mediating the activation of PKB by insulin and growth factors.
2,866 citations
TL;DR: The central hypothesis is that the AMP-activated protein kinase cascade appears to be an ancient system which evolved to protect cells against the effects of nutritional or environmental stress, and protects the cell by switching off ATP-consuming pathways and switching on alternative pathways for ATP generation.
Abstract: A single entity, the AMP-activated protein kinase (AMPK), phosphorylates and regulates in vivo hydroxymethylglutaryl-CoA reductase and acetyl-CoA carboxylase (key regulatory enzymes of sterol synthesis and fatty acid synthesis, respectively), and probably many additional targets. The kinase is activated by high AMP and low ATP via a complex mechanism, which involves allosteric regulation, promotion of phosphorylation by an upstream protein kinase (AMPK kinase), and inhibition of dephosphorylation. This protein-kinase cascade represents a sensitive system, which is activated by cellular stresses that deplete ATP, and thus acts like a cellular fuel gauge. Our central hypothesis is that, when it detects a 'low-fuel' situation, it protects the cell by switching off ATP-consuming pathways (e.g. fatty acid synthesis and sterol synthesis) and switching on alternative pathways for ATP generation (e.g. fatty acid oxidation). Native AMP-activated protein kinase is a heterotrimer consisting of a catalytic alpha subunit, and beta and gamma subunits, which are also essential for activity. All three subunits have homologues in budding yeast, which are components of the SNF1 protein-kinase complex. SNF1 is activated by glucose starvation (which in yeast leads to ATP depletion) and genetic studies have shown that it is involved in derepression of glucose-repressed genes. This raises the intriguing possibility that AMPK may regulate gene expression in mammals. AMPK/SNF1 homologues are found in higher plants, and this protein-kinase cascade appears to be an ancient system which evolved to protect cells against the effects of nutritional or environmental stress.
1,310 citations
TL;DR: This review represents an update of the nomenclature system for the UDP glucuronosyltransferase gene superfamily, which is based on divergent evolution and is anticipated that this UGT gene nomenClature system will require updating on a regular basis.
Abstract: This review represents an update of the nomenclature system for the UDP glucuronosyltransferase gene superfamily, which is based on divergent evolution. Since the previous review in 1991, sequences of many related UDP glycosyltransferases from lower organisms have appeared in the database, which expand our database considerably. At latest count, in animals, yeast, plants and bacteria there are 110 distinct cDNAs/genes whose protein products all contain a characteristic 'signature sequence' and, thus, are regarded as members of the same superfamily. Comparison of a relatedness tree of proteins leads to the definition of 33 families. It should be emphasized that at least six cloned UDP-GlcNAc N-acetylglucosaminyltransferases are not sufficiently homologous to be included as members of this superfamily and may represent an example of convergent evolution. For naming each gene, it is recommended that the root symbol UGT for human (Ugt for mouse and Drosophila), denoting 'UDP glycosyltransferase,' be followed by an Arabic number representing the family, a letter designating the subfamily, and an Arabic numeral denoting the individual gene within the family or subfamily, e.g. 'human UGT2B4' and 'mouse Ugt2b5'. We recommend the name 'UDP glycosyltransferase' because many of the proteins do not preferentially use UDP glucuronic acid, or their nucleotide sugar preference is unknown. Whereas the gene is italicized, the corresponding cDNA, transcript, protein and enzyme activity should be written with upper-case letters and without italics, e.g. 'human or mouse UGT1A1.' The UGT1 gene (spanning > 500 kb) contains at least 12 promoters/first exons, which can be spliced and joined with common exons 2 through 5, leading to different N-terminal halves but identical C-terminal halves of the gene products; in this scheme each first exon is regarded as a distinct gene (e.g. UGT1A1, UGT1A2, ... UGT1A12). When an orthologous gene between species cannot be identified with certainty, as occurs in the UGT2B subfamily, sequential naming of the genes is being carried out chronologically as they become characterized. We suggest that the Human Gene Nomenclature Guidelines (http://www.gene.acl.ac.uk/nomenclature/guidelines.html++ +) be used for all species other than the mouse and Drosophila. Thirty published human UGT1A1 mutant alleles responsible for clinical hyperbilirubinemias are listed herein, and given numbers following an asterisk (e.g. UGT1A1*30) consistent with the Human Gene Nomenclature Guidelines. It is anticipated that this UGT gene nomenclature system will require updating on a regular basis.
1,075 citations
TL;DR: The results indicate that PI3-K activity is required for translocation of PKB to the plasma membrane, where its activation occurs through phosphorylation of the same sites that are induced by insulin or IGF-1.
1,059 citations
TL;DR: Evidence is provided that decreases in muscle content of malonyl-CoA can increase the rate of fatty acid oxidation, and perfusion with medium containing AICAR was found to activate AMPK in skeletal muscle, inactivate ACC, and decrease malony l-coA.
Abstract: 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) has previously been reported to be taken up into cells and phosphorylated to form ZMP, an analog of 5′-AMP This study was designed to determin
1,012 citations
TL;DR: In this article, it was found that nepovirus infection of nontransgenic plants induces a resistance mechanism that is similar to transgene-induced gene silencing, which may be related to natural defense against viruses.
Abstract: Gene silencing in plants, in which an endogenous gene is suppressed by introduction of a related transgene, has been used for crop improvement. Observations that viruses are potentially both initiators and targets of gene silencing suggested that this phenomenon may be related to natural defense against viruses. Supporting this idea, it was found that nepovirus infection of nontransgenic plants induces a resistance mechanism that is similar to transgene-induced gene silencing.
865 citations
TL;DR: Although peptides derived from exogenous protein sources are usually excluded from presentation on class I MHC molecules, recent evidence shows that this embargo may be lifted in certain professional antigen-presenting cells to increase the spectrum of antigens that may be displayed on class II MHC.
Abstract: Class I and class II MHC molecules bind peptides during their biosynthetic maturation and provide a continuously updated display of intracellular and environmental protein composition, respectively, for scrutiny by T cells. Receptor-mediated endocytosis, phagocytosis, and macropinocytosis all contribute to antigen uptake by class II MHC-positive antigen-presenting cells. Capture of antigenic peptides by class II MHC molecules is facilitated because antigen catabolism and class II MHC maturation take place in the same compartments or in communicating compartments of the endosome/lysosome system. These class II MHC-rich, multivesicular endosomes receive incoming antigen and can support not only antigen processing and class II MHC peptide loading but also the export of peptide/class II MHC complexes to the cell surface. A balance between production and destruction of antigenic peptides is achieved by the activity of local proteases and may be influenced by binding of antigen to other proteins both prior to the onset of processing (e.g. antibodies) and during antigen unfolding (e.g. MHC molecules). T cell determinants that can be released for MHC binding without a substantial processing requirement may be able to utilize a distinct minor population of cell surface class II MHC molecules that become available during peripheral recycling. Although peptides derived from exogenous protein sources are usually excluded from presentation on class I MHC molecules, recent evidence shows that this embargo may be lifted in certain professional antigen-presenting cells to increase the spectrum of antigens that may be displayed on class I MHC.
809 citations
TL;DR: Human PDK1 is homologous to the Drosophila protein kinase DSTPK61, which has been implicated in the regulation of sex differentiation, oogenesis and spermatogenesis and is likely to mediate the activation of PKB by insulin or growth factors.
751 citations
TL;DR: The findings identify a recognition site on PP1c, invariant from yeast to humans, for a critical structural motif on regulatory subunit that explains why the binding of PP1 to its regulatory subunits is mutually exclusive, and suggests a novel approach for identifying the functions of PP 1‐binding proteins whose roles are unknown.
Abstract: The diverse forms of protein phosphatase 1 in vivo result from the association of its catalytic subunit (PP1c) with different regulatory subunits, one of which is the G‐subunit (G M ) that targets PP1c to glycogen particles in muscle Here we report the structure, at 30 A resolution, of PP1c in complex with a 13 residue peptide (G M[63–75] ) of G M The residues in G M[63–75] that interact with PP1c are those in the Arg/Lys–Val/Ile–Xaa–Phe motif that is present in almost every other identified mammalian PP1‐binding subunit Disrupting this motif in the G M[63–75] peptide and the M 110[1–38] peptide (which mimics the myofibrillar targeting M 110 subunit in stimulating the dephosphorylation of myosin) prevents these peptides from interacting with PP1 A short peptide from the PP1‐binding protein p53BP2 that contains the RVXF motif also interacts with PP1c These findings identify a recognition site on PP1c, invariant from yeast to humans, for a critical structural motif on regulatory subunits This explains why the binding of PP1 to its regulatory subunits is mutually exclusive, and suggests a novel approach for identifying the functions of PP1‐binding proteins whose roles are unknown
609 citations
TL;DR: The present research reports the development and validation of a universal inventory that equips health professions/medical educators with a diagnostic tool to measure the state of their school's learning and teaching climate.
Abstract: The General Medical Council has initiated major innovations in the undergraduate medical curriculum. These requirements are forcing a rapid rate of change in medical schools throughout the UK which parallels many developments in North America. There have also been several international and national mission statements which call for similar reforms in education in the health professions. While the improvement of the learning environment and 'climate' is a major goal of the changes, the very rate of change is itself stressful. The present research reports the development and validation of a universal inventory that equips health professions/medical educators with a diagnostic tool to measure the state of their school's learning and teaching climate.
591 citations
TL;DR: Recent progress in understanding some of the functions of these enzymes that has been made possible by the introduction of some novel approaches, particularly the use of two specific inhibitors.
TL;DR: In this paper, the authors propose a conceptual framework for the development of social accounting by organizations, and draw out best practice from a range of different social accounting experiments, illustrated by reference to two short cases from Traidcraft plc and TraidCraft Exchange.
Abstract: Addresses three related, though not entirely congruent, aims. Seeks, first, to initiate moves towards a “normative theory” ‐ a conceptual framework ‐ for the developing of social accounting by organizations. Second, aims inductively to draw out best practice from a range of social accounting experiments, illustrated, in particular, by reference to two short cases from Traidcraft plc and Traidcraft Exchange. Third, draws from the conclusions reached in the exploration of the first two aims and attempts to identify any clear “social accounting standards” or “generally acceptable social accounting principles” which can be used to guide the new and emerging social accounting practice. Presents a number of subtexts which attempt to link back to the accounting literature’s more trenchant critiques of social accounting; to address the tension between academic theorizing and engaging with practice; to synthesize different approaches to social accounting practice; and to respond to the urgency that the recent upsurge in interest in social accounting places on the newly formed Institute of Social and Ethical Accountability. An ambitious paper which means that coverage of issues must be thinner than might typically be expected ‐ exploratory, rather than providing answer, offers a collective view from experience and encourage engagement with the rapidly evolving social accounting agenda.
TL;DR: Many novel protein serine/threonine phosphatases in the PPP family have recently been discovered and the insights that have been gained into their different functions are summarised in this review.
TL;DR: It is suggested that poor adherence to insulin treatment is the major factor that contributes to long-term poor glycaemic control and diabetic ketoacidosis in patients aged 10-20 years.
TL;DR: A polymerase chain reaction (PCR)-based method which exploits this polymorphism for the generation of molecular markers in barley, which produces amplified fragments containing a Bare–1-like retrotransposon long terminal repeat (LTR) sequence at one end and a flanking host restriction site at the other.
Abstract: Retrotransposons are present in high copy number in many plant genomes. They show a considerable degree of sequence heterogeneity and insertional polymorphism, both within and between species. We describe here a polymerase chain reaction (PCR)-based method which exploits this polymorphism for the generation of molecular markers in barley. The method produces amplified fragments containing a Bare–1-like retrotransposon long terminal repeat (LTR) sequence at one end and a flanking host restriction site at the other. The level of polymorphism is higher than that revealed by amplified fragment length polymorphism (AFLP) in barley. Segregation data for 55 fragments, which were polymorphic in a doubled haploid barley population, were analysed alongside an existing framework of some 400 other markers. The markers showed a widespread distribution over the seven linkage groups, which is consistent with the distribution of the Bare–1 class of retrotransposons in the barley genome based on in situ hybridisation data. The potential applicability of this method to the mapping of other multicopy sequences in plants is discussed.
TL;DR: It is proposed that PKB is part of the insulin signaling cascade for PFK-2 activation in heart and phosphorylated Ser-466 and Ser-483 in the BH1 isoform, but to different extents.
TL;DR: The results suggest that cellular functions previously attributed to SAPK1 and/or SAPK2 may be mediated by SAPK3 or SAPK4.
Abstract: A cDNA was cloned that encodes human stress-activated protein kinase-4 (SAPK4), a novel MAP kinase family member whose amino acid sequence is approximately 60% identical to that of the other three SAP kinases which contain a TGY motif in their activation domain. The mRNA encoding SAPK4 was found to be widely distributed in human tissues. When expressed in KB cells, SAPK4 was activated in response to cellular stresses and pro-inflammatory cytokines, in a manner similar to other SAPKs. SAPK4 was activated in vitro by SKK3 (also called MKK6) or when co-transfected with SKK3 into COS cells. SKK3 was the only activator of SAPK4 that was induced when KB cells were exposed to a cellular stress or stimulated with interleukin-1. These findings indicate that SKK3 mediates the activation of SAPK4. The substrate specificity of SAPK4 in vitro was similar to that of SAPK3. Both enzymes phosphorylated the transcription factors ATF2, Elk-1 and SAP-1 at similar rates, but were far less effective than SAPK2a (also called RK/p38) or SAPK2b (also called p38beta) in activating MAPKAP kinase-2 and MAPKAP kinase-3. Unlike SAPK1 (also called JNK), SAPK3 and SAPK4 did not phosphorylate the activation domain of c-Jun. Unlike SAPK2a and SAPK2b, SAPK4 and SAPK3 were not inhibited by the drugs SB 203580 and SB 202190. Our results suggest that cellular functions previously attributed to SAPK1 and/or SAPK2 may be mediated by SAPK3 or SAPK4.
TL;DR: Evidence that the sugar conformation is strained is presented and it is proposed that this originates from forces that optimize guanine base stacking, which results from a simple crankshaft rotation that requires no net change in theugar conformation.
TL;DR: Observations provide evidence that PKBβ undergoes nuclear translocation upon mitogenic activation and support a role for PKB in signaling from receptor tyrosine kinases to the nucleus through phosphatidylinositol 3-kinase.
TL;DR: These experiments indicate that SAPKK3 mediates the activation of SAPK3 in several mammalian cells and suggest that cellular functions previously attributed to SAPK1 and/or SAPK2 may be mediated by SAPK 3.
Abstract: Stress-activated protein kinase-3 (SAPK3), a recently described MAP kinase family member with a wide-spread tissue distribution, was transfected into several mammalian cell lines and shown to be activated in response to cellular stresses, interleukin-1 (IL-1) and tumour necrosis factor (TNF) in a similar manner to SAPK1 (also termed JNK) and SAPK2 (also termed p38, RK, CSBP and Mxi2). SAPK3 and SAPK2 were activated at similar rates in vitro by SAPKK3 (also termed MKK6), and SAPKK3 was the only activator of SAPK3 that was induced when KB or 293 cells were exposed to cellular stresses or stimulated with IL-1 or TNF. Co-transfection with SAPKK3 induced SAPK3 activity and greatly enhanced activation in response to osmotic shock. These experiments indicate that SAPKK3 mediates the activation of SAPK3 in several mammalian cells. SAPK3 and SAPK2 phosphorylated a number of proteins at similar rates, including the transcription factors ATF2, Elk-1 and SAP1, but SAPK3 was far less effective than SAPK2 in activating MAPKAP kinase-2 and MAPKAP kinase-3. Unlike SAPK2, SAPK3 was not inhibited by the drug SB 203580. SAPK3 phosphorylated ATF2 at Thr69, Thr71 and Ser90, the same residues phosphorylated by SAPK1, whereas SAPK2 only phosphorylated Thr69 and Thr71. Our results suggest that cellular functions previously attributed to SAPK1 and/or SAPK2 may be mediated by SAPK3.
TL;DR: The mini protein approach provides a powerful new method to activate p53 without causing DNA damage and establishes a powerful general method for determining the biological consequences of the specific disruption of protein-protein interactions in cells.
TL;DR: It is shown that BMDC exhibit high levels of macropinocytosis driven by constitutive membrane ruffling activity, and exogenous ovalbumin presented to a T cell hybridoma more effectively, more rapidly, and at lower exogenous antigen concentrations than BM macrophages on a cell‐for‐cell basis.
Abstract: Dendritic cells expanded from mouse bone marrow (BMDC) with granulocyte/macrophage-colony-stimulating factor have potent T cell-stimulatory properties both in vitro and in vivo. This has been well documented for major histocompatibility complex (MHC) class II-restricted responses, and more recently using peptide-loaded and protein-pulsed DC for CD8 responses following adoptive transfer in mice. An unresolved question concerns the capacity of BMDC to present exogenous antigen on MHC class I molecules, an unconventional mode of MHC class I loading for which there is now considerable evidence, particularly in macrophages. Here, we show that BMDC exhibit high levels of macropinocytosis driven by constitutive membrane ruffling activity. Up to one-third of actively ruffling and macropinocytosing BMDC transferred pinocytosed horseradish peroxidase into the cytosol following a 15-min pulse, suggesting that they might be capable of presenting exogenous soluble antigen on MHC class I molecules. We show that BMDC presented exogenous ovalbumin to a T cell hybridoma more effectively, more rapidly, and at lower exogenous antigen concentrations than BM macrophages on a cell-for-cell basis. Presentation was TAP dependent, brefeldin A sensitive, and blocked by inhibitors of proteasomal processing, demonstrating use of the classical MHC class I pathway. Although effective presentation of exogenous antigen by BMDC occurred in the absence of agents which stimulate macropinocytosis, treatment with phorbol myristate acetate (PMA) enhanced both pinocytosis and MHC class I presentation by BMDC. Finally, PMA-stimulated BMDC exposed to exogenous ovalbumin in vitro were able to prime an antigen-specific cytotoxic T lymphocyte response following adoptive transfer in vivo.
TL;DR: The molecular findings and clinical observations in this patient attest to the dual importance of plakophilin 1 in both cutaneous cell–cell adhesion and epidermal morphogenesis.
Abstract: Members of the armadillo protein gene family, which includes plakoglobin and beta-catenin, have important functions in cytoskeleton/cell membrane interactions. These proteins may act as linker molecules at adherens junctions and desmosomes at the plasma membrane; in addition, they may have pivotal roles in signal transduction pathways and significant effects on cell behaviour during development. Here, we describe the first human mutations in one of these dual function proteins, plakophilin 1 (band-6 protein; refs 8-10). The affected individual has a complete absence of immunostaining for plakophilin 1 in the skin and is a compound heterozygote for autosomal-recessively inherited premature termination codons of translation on both alleles of the plakophilin 1 gene (PKP1). Clinically, there are features of both cutaneous fragility and congenital ectodermal dysplasia affecting skin, hair and nails. There is no evidence of significant abnormalities in other epithelia or tissues. Desmosomes in the skin are small and poorly formed with widening of keratinocyte intercellular spaces and perturbed desmosome/keratin intermediate filament interactions. The molecular findings and clinical observations in this patient attest to the dual importance of plakophilin 1 in both cutaneous cell-call adhesion and epidermal morphogenesis.
TL;DR: The mammalian sequences are clearly homologous with legumains from non-mammalian species and the significance of the discovery of a cysteine endopeptidase of a new family and distinctive specificity in man and other mammals is discussed.
TL;DR: These are the first human data to show that use of the aldosterone antagonist, spironolactone, can positively improve time-domain heart rate variability and reduce myocardial collagen turnover, as reflected by further reductions in serum procollagen peptide, despite concurrent ACE inhibitor treatment.
Abstract: Background: Experimental data suggest that aldosterone has harmful effects promoting myocardial fibrosis and disturbing autonomic balance. There has been no evidence of these potential effects in intact man. Methods and Results: We report the findings in 31 patients with stable chronic heart failure (CHF) who were treated with spironolactone (50–100 mg/day) or placebo in addition to diuretics and angiotensin converting enzyme (ACE) inhibition. In a controlled randomised double-blind study, we found that spironolactone treatment reduced circulating levels of procollagen type III N-terminal amino peptide, a marker of vascular collagen turnover, and in addition increased time-domain parameters of heart rate variability ( n = 24). These latter parameters suggest a parasympathomimetic effect for additional spironolactone. Spironolactone significantly reduced heart rate (prolonged RR interval) particularly during the dawn hours (06.00–09.00 h). In this unbalanced study it was not possible to provide a detailed diurnal assessment of the impact of spironolactone on heart rate variability, but the preliminary data suggest that there may be an interaction with the autonomic nervous system which varies in time. Conclusions: These are the first human data to show that use of the aldosterone antagonist, spironolactone, can positively improve time-domain heart rate variability and reduce myocardial collagen turnover, as reflected by further reductions in serum procollagen peptide, despite concurrent ACE inhibitor treatment. Residual aldosterone after ACE inhibitor treatment may therefore have a role promoting arrhythmia and cardiac death by two mechanisms. Effects of additional spironolactone on slowing heart rate (and potentially the detrimental effect of aldosterone) were most prominent between 6 a.m. and 10 a.m. when cardiac death is also known to be most prominent.
TL;DR: Preliminary evidence is found that beta 2-adrenoceptor polymorphism is associated with altered beta 1-adRenoceptor expression in asthma patients, and the homozygous Gly-16 form was significantly more prone to bronchodilator desensitisation than Arg 16, with the influence of Gly 16 dominating over any putative protective effects of Glu 27.
TL;DR: Three selected aspects which illustrate the key importance of microorganisms in effecting changes in metal(loid) solubility are illustrated, namely toxic metal sulfide precipitation by sulfate-reducing bacteria, heterotrophic leaching by fungi, and microbial transformations of metalloids, which includes reduction and methylation.
Abstract: Microorganisms play important roles in the environmental fate of toxic metals with a multiplicity of physico-chemical and biological mechanisms effecting transformations between soluble and insoluble phases. Such mechanisms are important components of natural biogeochemical cycles for metals and metalloids with some processes being of potential application to the treatment of contaminated materials. This paper will concentrate on three selected aspects which illustrate the key importance of microorganisms in effecting changes in metal(loid) solubility, namely toxic metal sulfide precipitation by sulfate-reducing bacteria, heterotrophic leaching by fungi, and microbial transformations of metalloids, which includes reduction and methylation. The basic microbiology of these processes is described as well as their environmental significance and use in bioremediation.
TL;DR: Electronic record linkage was more sensitive than general practice registers in identifying diabetic subjects and identified an additional 0.18% of the population with a history of hyperglycaemia who might warrant screening for undiagnosed diabetes.
Abstract: Objectives: To identify all patients with diabetes in a community using electronic record linkage of multiple data sources and to compare this method of case ascertainment with registers of diabetic patients derived from primary care. Design: Electronic capture-recapture linkage of records included data on all patients attending hospital diabetes clinics, all encashed prescriptions for diabetes related drugs and monitoring equipment, all patients discharged from hospital, patients attending a mobile unit for eye screening, and results for glycated haemoglobin and plasma glucose concentrations from the regional biochemistry database. Diabetes registers from primary care were from a random sample of eight Tayside general practices. A detailed manual study of relevant records for the 35 144 patients registered with these eight general practices allowed for validation of the case ascertainment. Setting: Tayside region of Scotland, population 391 274 on 1 January 1996. Main outcome measures: Prevalence of diabetes; population of patients identified by different data sources; sensitivity and positive predictive value of ascertainment methods. Results: Electronic record linkage identified 7596 diabetic patients, giving a prevalence of known diabetes of 1.94% (0.21% insulin dependent diabetes, 1.73% non-insulin dependent): 63% of patients had attended hospital diabetes clinics, 68% had encashed diabetes related prescriptions, 72% had attended the mobile eye screening unit, and 48% had biochemical results diagnostic of diabetes. A further 701 patients had isolated hyperglycaemia (plasma glucose >11.1 mmol/l) but were not considered diabetic by general practitioners. Validation against the eight general practices (636 diabetic patients) showed electronic linkage to have a sensitivity of 0.96 and a positive predictive value of 0.95 for ascertainment of known diabetes. General practice lists had a sensitivity of 0.91 and a positive predictive value of 0.98. Conclusions: Electronic record linkage was more sensitive than general practice registers in identifying diabetic subjects and identified an additional 0.18% of the population with a history of hyperglycaemia who might warrant screening for undiagnosed diabetes. Key messages It has been recommended that regional registers of patients with diabetes are established in order to facilitate effective monitoring and treatment of diabetes In Tayside we created a diabetes register by record linkage of multiple data sources: all patients attending hospital diabetes clinics, all encashed prescriptions for diabetes related drugs and monitoring equipment, all patients discharged from hospital, patients attending a mobile unit for eye screening, and results for glycated haemoglobin and plasma glucose concentrations from the regional biochemistry database This register identified 7596 patients with diabetes in Tayside, giving a prevalence of diabetes of 1.94% Record linkage was more sensitive than general practice registers in ascertaining cases of known diabetes A unique patient identifier, the community health number, was fundamental for successful record linkage
TL;DR: It is proposed that tumour lines which express high levels of transcriptionally inactive mutant p53 are unable to induce the expression of the Mdm2 protein which would normally provide a feedback mechanism down-regulating p53 protein levels in the absence of DNA damage signals.
Abstract: The tumour suppressor protein p53 is expressed at very low levels in normal cells but accumulates in response to DNA damaging agents such as u.v. irradiation. This increase is accompanied by transcriptional upregulation of the expression of a number of proteins including Mdm2 which can in turn inhibit p53 dependent transcriptional activation, creating a feedback loop resulting in down-regulation of p53 activity. Mutant p53 proteins are however frequently detected at constitutively high levels in many tumours and tumour cell lines, indeed this phenomenon has been used in several studies to diagnose p53 mutation in patient tumours. We show here that expression of mouse mutant p53 in tumour cell lines of this type results in high levels of both the endogenous p53 protein and the exogenously expressed mutant mouse protein, whereas the human tumour line MCF7 does not exhibit high levels of either endogenous human or exogenously expressed mouse mutant p53 unless stabilisation is induced by DNA damage. This suggests that the stability of mutant p53 is not intrinsic to mutant p53 protein structure but may vary in different cell backgrounds. We present evidence that p53 protein stability in tumour cell lines is determined by association with the Mdm2 tumour suppressor protein, and that p53 mutants which are unable to bind Mdm2 are stable in MCF7 cells. We propose that tumour lines which express high levels of transcriptionally inactive mutant p53 are unable to induce the expression of the Mdm2 protein which would normally provide a feedback mechanism down-regulating p53 protein levels in the absence of DNA damage signals. MCF7 cells however express a transcriptionally active p53 and retain the feedback regulation of p53 protein levels by Mdm2.
TL;DR: These findings double the number of candidate protein kinases for the hyperphosphorylation of tau in Alzheimer's disease and other neurodegenerative disorders.