University of Dundee

About: University of Dundee is a education organization based out in Dundee, United Kingdom. It is known for research contribution in the topics: Population & Protein kinase A. The organization has 19258 authors who have published 39640 publications receiving 1919433 citations. The organization is also known as: Universitas Dundensis & Dundee University.

Polo-like kinases: a team that plays throughout mitosis

Abstract: When the first mutant allele of the Drosophila genepolo was first characterized over 10 years ago, attention focused on the defects that centrosome behavior exhibited at various stages of development (Sunkel and Glover 1988). The subsequent realization that the serine-threonine kinase it encodes is highly conserved from yeasts to humans has provoked a flurry of investigation into the function of the enzyme. A role for the polo-like kinases (plks) in regulating centrosome behavior has been borne out in several organisms, and the enzymes have attracted further attention recently with the realization that they regulate multiple stages of mitotic progression. In this article we review the current status of our understanding of the functions of plks from the time of commitment to M phase in the activation of Cdc25, through the activation of the anaphase promoting complex (APC), to the regulation of late mitotic events essential for cytokinesis. We discuss how to reconcile the sometimes apparently disparate observations made upon plk function in different organisms.

The inhibition of glycogen synthase kinase-3 by insulin or insulin-like growth factor 1 in the rat skeletal muscle cell line L6 is blocked by wortmannin, but not by rapamycin: evidence that wortmannin blocks activation of the mitogen-activated protein kinase pathway in L6 cells between Ras and Raf

Abstract: Glycogen synthase kinase-3 (GSK3) is inactivated in vitro by p70 S6 kinase or MAP kinase-activated protein kinase-1 beta (MAPKAP kinase-1 beta; also known as Rsk-2). Here we show that GSK3 isoforms are inhibited by 40% within minutes after stimulation of the rat skeletal-muscle cell line L6 with insulin-like growth factor-1 (IGF-1) or insulin. GSK3 was similarly inhibited in rabbit skeletal muscle after an intravenous injection of insulin. Inhibition resulted from increased phosphorylation of GSK3, probably at a serine/threonine residue(s), because it was reversed by incubation with protein phosphatase-2A. Rapamycin blocked the activation of p70 S6 kinase by IGF-1 in L6 cells, but had no effect on the inhibition of GSK3 or the activation of MAPKAP kinase-1 beta. In contrast, wortmannin, a potent inhibitor of PtdIns 3-kinase, prevented the inactivation of GSK3 and the activation of MAPKAP kinase-1 beta and p70 S6 kinase by IGF-1 or insulin. Wortmannin also blocked the activation of p74raf-1. MAP kinase kinase and p42 MAP kinase, but not the formation of GTP-Ras by IGF-1. The results suggest that the stimulation of glycogen synthase by insulin/IGF-1 in skeletal muscle involves the MAP-KAP kinase-1-catalysed inhibition of GSK3, as well as the previously described activation of the glycogen-associated form of protein phosphatase-1.

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals

Abstract: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

Adherence to prescribed oral hypoglycaemic medication in a population of patients with Type 2 diabetes: a retrospective cohort study.

Abstract: Aims To evaluate the patterns and predictors of adherence in all patients with Type 2 diabetes in the community receiving treatment with a single oral hypoglycaemic drug. In particular, to test the hypothesis that one tablet per day is associated with better adherence than more than one. Methods The study design was a retrospective cohort study set in the Tayside region of Scotland (population approx. 400 000). Participants were residents of Tayside from 1 January 1993 until 31 December 1995 with at least 12 months of prescriptions of oral hypoglycaemic drugs (OHDs). The main outcome measures were adherence indices for sulphonylureas and metformin separately, adjusting for prescribing while hospitalized. Results Of the total 2920 subjects identified, adequate adherence ( ≥ 90%) was found in 31% of those prescribed sulphonylureas alone ( n = 1329, median adherence = 300 days per year), and in 34% of those prescribed metformin alone ( n = 528, median = 302 days per year). There were significant linear trends of poorer adherence with each increase in the daily number of tablets taken ( p = 0.001) and increase in co-medication ( p = 0.0001) for sulphonylureas alone after adjustment for other factors. Conclusions In the community only one in three with Type 2 diabetes had adequate adherence to OHDs. One tablet per day administration was associated with greater adherence than multiple tablets. Poor adherence is a major obstacle to the benefit of complex drug regimens in the treatment of Type 2 diabetes.

Yeast kinesin-8 depolymerizes microtubules in a length-dependent manner

Abstract: The microtubule cytoskeleton and the mitotic spindle are highly dynamic structures, yet their sizes are remarkably constant, thus indicating that the growth and shrinkage of their constituent microtubules are finely balanced. This balance is achieved, in part, through kinesin-8 proteins (such as Kip3p in budding yeast and KLP67A in Drosophila) that destabilize microtubules. Here, we directly demonstrate that Kip3p destabilizes microtubules by depolymerizing them--accounting for the effects of kinesin-8 perturbations on microtubule and spindle length observed in fungi and metazoan cells. Furthermore, using single-molecule microscopy assays, we show that Kip3p has several properties that distinguish it from other depolymerizing kinesins, such as the kinesin-13 MCAK. First, Kip3p disassembles microtubules exclusively at the plus end and second, remarkably, Kip3p depolymerizes longer microtubules faster than shorter ones. These properties are consequences of Kip3p being a highly processive, plus-end-directed motor, both in vitro and in vivo. Length-dependent depolymerization provides a new mechanism for controlling the lengths of subcellular structures.