Linked Life Data

18042735

Source:http://linkedlifedata.com/resource/pubmed/id/18042735

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2008-2-22
pubmed:abstractText
Post-transplant diabetes is an untoward effect often observed under immunosuppressive therapy with cyclosporin A. Besides the development of peripheral insulin resistance and a decrease in insulin gene transcription, a beta-cell toxic effect has been described. However, its molecular mechanism remains unknown. In the present study, the effect of cyclosporin A and the dual leucine-zipper-bearing kinase (DLK) on beta-cell survival was investigated. Cyclosporin A decreased the viability of the insulin-producing pancreatic islet cell line HIT in a time- and concentration-dependent manner. Upon exposure to the immunosuppressant fragmentation of DNA, the activation of the effector caspase-3 and a decrease of full-length caspase-3 and Bcl(XL) were observed in HIT cells and in primary mature murine islets, respectively. Cyclosporin A and tacrolimus, both potent inhibitors of the calcium/calmodulin-dependent phosphatase calcineurin, stimulated the enzymatic activity of cellular DLK in an in vitro kinase assay. Immunocytochemistry revealed that the overexpression of DLK but not its kinase-dead mutant induced apoptosis and enhanced cyclosporin A-induced apoptosis to a higher extent than the drug alone. Moreover, in the presence of DLK, the effective concentration for cyclosporin A-caused apoptosis was similar to its known IC(50) value for the inhibition of calcineurin activity in beta cells. These data suggest that cyclosporin A through inhibition of calcineurin activates DLK, thereby leading to beta-cell apoptosis. This action may thus be a novel mechanism through which cyclosporin A precipitates post-transplant diabetes.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1521-0111
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
73
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
652-9
pubmed:dateRevised
2011-11-2
pubmed:meshHeading
pubmed-meshheading:18042735-Animals, pubmed-meshheading:18042735-Apoptosis, pubmed-meshheading:18042735-Calcineurin, pubmed-meshheading:18042735-Caspase 3, pubmed-meshheading:18042735-Cell Death, pubmed-meshheading:18042735-Cell Line, pubmed-meshheading:18042735-Cell Survival, pubmed-meshheading:18042735-Cyclosporine, pubmed-meshheading:18042735-DNA Fragmentation, pubmed-meshheading:18042735-Dose-Response Relationship, Drug, pubmed-meshheading:18042735-Enzyme Activation, pubmed-meshheading:18042735-Formazans, pubmed-meshheading:18042735-Immunohistochemistry, pubmed-meshheading:18042735-Immunosuppressive Agents, pubmed-meshheading:18042735-Inhibitory Concentration 50, pubmed-meshheading:18042735-Insulin-Secreting Cells, pubmed-meshheading:18042735-Kinetics, pubmed-meshheading:18042735-MAP Kinase Kinase Kinases, pubmed-meshheading:18042735-Mice, pubmed-meshheading:18042735-Statistics as Topic, pubmed-meshheading:18042735-Tacrolimus, pubmed-meshheading:18042735-Tetrazolium Salts, pubmed-meshheading:18042735-bcl-X Protein
pubmed:year
2008
pubmed:articleTitle
Activation of the dual-leucine-zipper-bearing kinase and induction of beta-cell apoptosis by the immunosuppressive drug cyclosporin A.
pubmed:affiliation
Molecular Pharmacology, University of Göttingen, Robert-Koch-Str. 40, 37099 Göttingen, Germany.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't