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.

The WNK1 and WNK4 protein kinases that are mutated in Gordon's hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinases

Abstract: Mutations in the human genes encoding WNK1 [with no K (lysine) protein kinase-1] and the related protein kinase WNK4 are the cause of Gordon's hypertension syndrome. Little is known about the molecular mechanism by which WNK isoforms regulate cellular processes. We immunoprecipitated WNK1 from extracts of rat testis and found that it was specifically associated with a protein kinase of the STE20 family termed 'STE20/SPS1-related proline/alanine-rich kinase' (SPAK). We demonstrated that WNK1 and WNK4 both interacted with SPAK as well as a closely related kinase, termed 'oxidative stress response kinase-1' (OSR1). Wildtype (wt) but not catalytically inactive WNK1 and WNK4 phosphorylated SPAK and OSR1 to a much greater extent than with other substrates utilized previously, such as myelin basic protein and claudin-4. Phosphorylation by WNK1 or WNK4 markedly increased SPAK and OSR1 activity. Phosphopeptide mapping studies demonstrated that WNK1 phosphorylated kinase-inactive SPAK and OSR1 at an equivalent residue located within the T-loop of the catalytic domain (Thr233 in SPAK, Thr185 in OSR1) and a serine residue located within a C-terminal non-catalytic region (Ser373 in SPAK, Ser325 in OSR1). Mutation of Thr185 to alanine prevented the activation of OSR1 by WNK1, whereas mutation of Thr185 to glutamic acid (to mimic phosphorylation) increased the basal activity of OSR1 over 20-fold and prevented further activation by WNK1. Mutation of Ser325 in OSR1 to alanine or glutamic acid did not affect the basal activity of OSR1 or its ability to be activated by WNK1. These findings suggest that WNK isoforms operate as protein kinases that activate SPAK and OSR1 by phosphorylating the T-loops of these enzymes, resulting in their activation. Our analysis also describes the first facile assay that can be employed to quantitatively assess WNK1 and WNK4 activity.

Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk

Abstract: Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.

Risk factors for delayed presentation and referral of symptomatic cancer: evidence for common cancers

Abstract: It has been suggested that the known poorer survival from cancer in the United Kingdom, compared with other European countries, can be attributed to more advanced cancer stage at presentation. There is, therefore, a need to understand the diagnostic process, and to ascertain the risk factors for increased time to presentation. We report the results from two worldwide systematic reviews of the literature on patient-mediated and practitioner-mediated delays, identifying the factors that may influence these. Across cancer sites, non-recognition of symptom seriousness is the main patient-mediated factor resulting in increased time to presentation. There is strong evidence of an association between older age and patient delay for breast cancer, between lower socio-economic status and delay for upper gastrointestinal and urological cancers and between lower education level and delay for breast and colorectal cancers. Fear of cancer is a contributor to delayed presentation, while sanctioning of help seeking by others can be a powerful mediator of reduced time to presentation. For practitioner delay, ‘misdiagnosis’ occurring either through treating patients symptomatically or relating symptoms to a health problem other than cancer, was an important theme across cancer sites. For some cancers, this could also be linked to inadequate patient examination, use of inappropriate tests or failing to follow-up negative or inconclusive test results. Having sought help for potential cancer symptoms, it is therefore important that practitioners recognise these symptoms, and examine, investigate and refer appropriately.