Maass P.G.,Max Delbruck Centrum fur Molekulare Medizin MDC
Medizinische Genetik | Year: 2014
Long non-coding RNAs (lncRNAs) expand our knowledge of transcriptional or posttranscriptional gene regulation. In interaction with the nuclear architecture, lncRNAs are involved in fundamental biological mechanisms, such as imprinting, histone code regulation, gene activation, gene repression, lineage determinations, and cell proliferation. Associations with apparent phenotypes have been attributed to lncRNAs. The involvement of lncRNA in gene regulation and disease underscores the importance of lncRNA-mediated regulatory networks. Manipulating lncRNAs is a conceivable therapeutic strategy because of their tissue-specific expression and their selective target genes. © 2014 Springer-Verlag.
Willoughby D.,University of Cambridge |
Halls M.L.,University of Cambridge |
Everett K.L.,University of Cambridge |
Ciruela A.,University of Cambridge |
And 3 more authors.
Journal of Cell Science | Year: 2012
Adenylyl cyclase (AC) isoforms can participate in multimolecular signalling complexes incorporating A-kinase anchoring proteins (AKAPs). We recently identified a direct interaction between Ca2+-sensitive AC8 and plasma membrane-targeted AKAP79/150 (in cultured pancreatic insulin-secreting cells and hippocampal neurons), which attenuated the stimulation of AC8 by Ca2+ entry (Willoughby et al., 2010). Here, we reveal that AKAP79 recruits cAMP-dependent protein kinase (PKA) to mediate the regulatory effects of AKAP79 on AC8 activity. Modulation by PKA is a novel means of AC8 regulation, which may modulate or apply negative feedback to the stimulation of AC8 by Ca2+ entry. We show that the actions of PKA are not mediated indirectly via PKA-dependent activation of protein phosphatase 2A (PP2A) B56d subunits that associate with the N-terminus of AC8. By site-directed mutagenesis we identify Ser-112 as an essential residue for direct PKA phosphorylation of AC8 (Ser-112 lies within the N-terminus of AC8, close to the site of AKAP79 association). During a series of experimentally imposed Ca2+ oscillations, AKAP79-targeted PKA reduced the on-rate of cAMP production in wild-type but not non-phosphorylatable mutants of AC8, which suggests that the protein-protein interaction may provide a feedback mechanism to dampen the downstream consequences of AC8 activation evoked by bursts of Ca2+ activity. This finetuning of Ca2+-dependent cAMP dynamics by targeted PKA could be highly significant for cellular events that depend on the interplay of Ca2+ and cAMP, such as pulsatile hormone secretion and memory formation. © 2012. Published by The Company of Biologists Ltd.
Hubner C.A.,Friedrich - Schiller University of Jena |
Hubner C.A.,Universitatsklinikum Jena |
Schroeder B.C.,Max Delbruck Centrum fur Molekulare Medizin MDC |
Ehmke H.,Universitatsklinikum Hamburg Eppendorf
Pflugers Archiv European Journal of Physiology | Year: 2015
Recent studies suggest that primary changes in vascular resistance can cause sustained changes in arterial blood pressure. In this review, we summarize current knowledge about Cl− homeostasis in vascular smooth muscle cells. Within vascular smooth muscle cells, Cl− is accumulated above the electrochemical equilibrium, causing Cl− efflux, membrane depolarization, and increased contractile force when Cl− channels are opened. At least two different transport mechanisms contribute to raise [Cl−]i in vascular smooth muscle cells, anion exchange, and cation-chloride cotransport. Recent work suggests that TMEM16A-associated Ca2+-activated Cl− currents mediate Cl− efflux in vascular smooth muscle cells leading to vasoconstriction. Additional proteins associated with Cl− flux in vascular smooth muscle are bestrophins, which modulate vasomotion, the volume-activated LRRC8, and the cystic fibrosis transmembrane conductance regulator (CFTR). Cl− transporters and Cl− channels in vascular smooth muscle cells (VSMCs) significantly contribute to the physiological regulation of vascular tone and arterial blood pressure. © 2015, Springer-Verlag Berlin Heidelberg.
Max Delbruck Centrum Fur Molekulare Medizin Mdc | Date: 2013-11-25
The present invention relates to methods for isolating human forkhead box P3 (Foxp3+) CD4+ regulatory T cells (herein referred to a Foxp3+ Treg cells) from a sample containing (i) peripheral blood mononuclear cells (PBMCs), (ii) a lymphocyte containing fluid, or (iii) a lymphocyte containing tissue, a kit for isolating human Foxp3+ Treg cells, and the use of anti-CD49d antibody for the isolation of human Foxp3+ Treg cells.
Morelli G.,Max Planck Institute For Infektionsbiologie |
Morelli G.,Max Planck Institute For Molekulare Genetik |
Song Y.,Beijing Institute of Microbiology and Epidemiology |
Song Y.,University College Cork |
And 28 more authors.
Nature Genetics | Year: 2010
Plague is a pandemic human invasive disease caused by the bacterial agent Yersinia pestis. We here report a comparison of 17 whole genomes of Y. pestis isolates from global sources. We also screened a global collection of 286 Y. pestis isolates for 933 SNPs using Sequenom MassArray SNP typing. We conducted phylogenetic analyses on this sequence variation dataset, assigned isolates to populations based on maximum parsimony and, from these results, made inferences regarding historical transmission routes. Our phylogenetic analysis suggests that Y. pestis evolved in or near China and spread through multiple radiations to Europe, South America, Africa and Southeast Asia, leading to country-specific lineages that can be traced by lineage-specific SNPs. All 626 current isolates from the United States reflect one radiation, and 82 isolates from Madagascar represent a second radiation. Subsequent local microevolution of Y. pestis is marked by sequential, geographically specific SNPs. © 2010 Nature America, Inc. All rights reserved.