Linked Life Data

11598106

Source:http://linkedlifedata.com/resource/pubmed/id/11598106

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
51
pubmed:dateCreated
2001-12-17
pubmed:abstractText
The reversible inhibition of calcineurin (CaN), which is the only Ca(2+)/calmodulin-dependent protein Ser/Thr phosphatase, is thought to be a key functional event for most cyclosporin A (CsA)- and tacrolimus (FK506)-mediated biological effects. In addition to CaN inhibition, however, CsA and FK506 have multiple biochemical effects because of their action in a gain-of-function model that requires prior binding to immunophilic proteins. We screened a small molecule library for direct inhibitors of CaN using CaN-mediated dephosphorylation of (33)P-labeled 19-residue phosphopeptide substrate (RII phosphopeptide) as an assay and found the polyphenolic aldehyde gossypol to be a novel CaN inhibitor. Unlike CsA and FK506, gossypol does not require a matchmaker protein for reversible CaN inhibition with an IC(50) value of 15 microm. Gossypolone, a gossypol analog, showed improved inhibition of both RII phosphopeptide and p-nitrophenyl phosphate dephosphorylation with an IC(50) of 9 and 6 microm, respectively. In contrast, apogossypol hexaacetate was inactive. Gossypol acts noncompetitively, interfering with the binding site for the cyclophilin 18.CsA complex in CaN. In contrast to CsA and FK506, gossypol does not inactivate the peptidyl-prolyl-cis/trans-isomerase activity of immunophilins. Similar to CsA and FK506, T cell receptor signaling induced by phorbol 12-myristate 13-acetate/ionomycin is inhibited by gossypol in a dose-dependent manner, demonstrated by the inhibition of nuclear factor of activated T cell (NFAT) c1 translocation from the cytosol into the nucleus and suppression of NFAT-luciferase reporter gene activity.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
21
pubmed:volume
276
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
47914-21
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:11598106-Amino Acid Sequence, pubmed-meshheading:11598106-Animals, pubmed-meshheading:11598106-CD4-Positive T-Lymphocytes, pubmed-meshheading:11598106-CD8-Positive T-Lymphocytes, pubmed-meshheading:11598106-Calcineurin, pubmed-meshheading:11598106-Cattle, pubmed-meshheading:11598106-Cells, Cultured, pubmed-meshheading:11598106-Cyclic AMP-Dependent Protein Kinases, pubmed-meshheading:11598106-DNA-Binding Proteins, pubmed-meshheading:11598106-Enzyme Inhibitors, pubmed-meshheading:11598106-Genes, Reporter, pubmed-meshheading:11598106-Gossypol, pubmed-meshheading:11598106-Humans, pubmed-meshheading:11598106-Luciferases, pubmed-meshheading:11598106-Lymphocyte Activation, pubmed-meshheading:11598106-Molecular Sequence Data, pubmed-meshheading:11598106-NFATC Transcription Factors, pubmed-meshheading:11598106-Nuclear Proteins, pubmed-meshheading:11598106-Phosphorylation, pubmed-meshheading:11598106-Protein Transport, pubmed-meshheading:11598106-Substrate Specificity, pubmed-meshheading:11598106-Transcription Factors
pubmed:year
2001
pubmed:articleTitle
Reversible inhibition of calcineurin by the polyphenolic aldehyde gossypol.
pubmed:affiliation
Max Planck Research Unit for Enzymology of Protein Folding, Weinbergweg 22, Halle/Saale D-06120, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't