Linked Life Data

16554484

Source:http://linkedlifedata.com/resource/pubmed/id/16554484

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2006-3-23
pubmed:abstractText
Glial cell line-derived neurotrophic factor (GDNF) is an important neurotrophic factor that has therapeutic implications for neurodegenerative disorders. We previously showed that leucine-isoleucine (Leu-Ile), an analog of a dipeptide-like structure of FK506 (tacrolimus), induces GDNF expression both in vivo and in vitro. In this investigation, we sought to clarify the cellular mechanisms underlying the GDNF-inducing effect of this dipeptide. Leu-Ile transport was investigated using fluorescein isothiocyanate-Leu-Ile in cultured neurons, and the results showed the transmembrane mobility of this dipeptide. By liquid chromatography-mass spectrometry and quartz crystal microbalance assay, we identified heat shock cognate protein 70 as a protein binding specifically to Leu-Ile, and molecular modeling showed that the ATPase domain is the predicted binding site. Leu-Ile stimulated Akt phosphorylation, which was attenuated significantly by heat shock protein 90 (Hsp90) inhibitor geldanamycin (GA). Moreover, enhanced interaction between phosphorylated Akt and Hsp90 was detected by immunoprecipitation. Leu-Ile elicited an increase in cAMP response element binding protein (CREB) phosphorylation, which was inhibited by GA, indicating that CREB is a downstream target of Hsp90/Akt signaling. Leu-Ile elevated the levels of GDNF mRNA and protein expression, whereas inhibition of CREB blocked such effects. Leu-Ile promoted the binding activity of phosphorylated CREB with cAMP response element. These findings show that CREB plays a key role in transcriptional regulation of GDNF expression induced by Leu-Ile. In conclusion, Leu-Ile activates Hsp90/Akt/CREB signaling, which contributes to the upregulation of GDNF expression. It may represent a novel lead compound for the treatment of dopaminergic neurons or motoneuron diseases.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1529-2401
pubmed:author
pubmed:issnType
Electronic
pubmed:day
22
pubmed:volume
26
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3335-44
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:16554484-Animals, pubmed-meshheading:16554484-Binding Sites, pubmed-meshheading:16554484-Cell Membrane, pubmed-meshheading:16554484-Cells, Cultured, pubmed-meshheading:16554484-Cyclic AMP Response Element-Binding Protein, pubmed-meshheading:16554484-Dipeptides, pubmed-meshheading:16554484-Enzyme Inhibitors, pubmed-meshheading:16554484-Glial Cell Line-Derived Neurotrophic Factor, pubmed-meshheading:16554484-HSC70 Heat-Shock Proteins, pubmed-meshheading:16554484-HSP90 Heat-Shock Proteins, pubmed-meshheading:16554484-Hippocampus, pubmed-meshheading:16554484-Neurons, pubmed-meshheading:16554484-Phosphorylation, pubmed-meshheading:16554484-Protein Binding, pubmed-meshheading:16554484-Proto-Oncogene Proteins c-akt, pubmed-meshheading:16554484-RNA, Messenger, pubmed-meshheading:16554484-Rats, pubmed-meshheading:16554484-Signal Transduction, pubmed-meshheading:16554484-Tacrolimus, pubmed-meshheading:16554484-Up-Regulation
pubmed:year
2006
pubmed:articleTitle
An analog of a dipeptide-like structure of FK506 increases glial cell line-derived neurotrophic factor expression through cAMP response element-binding protein activated by heat shock protein 90/Akt signaling pathway.
pubmed:affiliation
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't