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rdf:type |
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lifeskim:mentions |
umls-concept:C0010734,
umls-concept:C0031715,
umls-concept:C0031716,
umls-concept:C0109317,
umls-concept:C0752312,
umls-concept:C1150579,
umls-concept:C1157380,
umls-concept:C1333192,
umls-concept:C1333340,
umls-concept:C1366882,
umls-concept:C1370600,
umls-concept:C1522290,
umls-concept:C1705767,
umls-concept:C1705791
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pubmed:issue |
22
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pubmed:dateCreated |
2005-5-30
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pubmed:abstractText |
Surfactant deficiency contributes to acute lung injury and may result from the elaboration of bioactive lipids such as oxysterols. We observed that the oxysterol 22-hydroxycholesterol (22-HC) in combination with its obligate partner, 9-cis-retinoic acid (9-cis-RA), decreased surfactant phosphatidylcholine (PtdCho) synthesis by increasing phosphorylation of the regulatory enzyme CTP:phosphocholine cytidylyltransferase-alpha (CCTalpha). Phosphorylation of CCTalpha decreased its activity. 22-HC/9-cis-RA inhibition of PtdCho synthesis was blocked by PD98059 or dominant-negative ERK (p42 kinase). Overexpression of constitutively active MEK1, the kinase upstream of p42 kinase, increased CCTalpha phosphorylation. Expression of truncated CCTalpha mutants lacking proline-directed sites within the C-terminal phosphorylation domain partially blocked oxysterol-mediated inhibition of PtdCho synthesis. Mutagenesis of Ser315 within CCTalpha was both required and sufficient to confer significant resistance to 22-HC/9-cis-RA inhibition of PtdCho synthesis. A novel putative ERK-docking domain N-terminal to this phosphoacceptor site was mapped within the CCTalpha membrane-binding domain (residues 287-300). The results are the first demonstration of a physiologically relevant phosphorylation site and docking domain within CCTalpha that serve as targets for ERKs, resulting in inhibition of surfactant synthesis.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Choline-Phosphate...,
http://linkedlifedata.com/resource/pubmed/chemical/DNA, Complementary,
http://linkedlifedata.com/resource/pubmed/chemical/Extracellular Signal-Regulated MAP...,
http://linkedlifedata.com/resource/pubmed/chemical/Flavonoids,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase 1,
http://linkedlifedata.com/resource/pubmed/chemical/PD 98059,
http://linkedlifedata.com/resource/pubmed/chemical/Pcyt1a protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylcholines,
http://linkedlifedata.com/resource/pubmed/chemical/Proline,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Steroid,
http://linkedlifedata.com/resource/pubmed/chemical/Sterols,
http://linkedlifedata.com/resource/pubmed/chemical/Surface-Active Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Tretinoin,
http://linkedlifedata.com/resource/pubmed/chemical/alitretinoin,
http://linkedlifedata.com/resource/pubmed/chemical/oxysterol receptor
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
3
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pubmed:volume |
280
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
21577-87
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:15788406-Animals,
pubmed-meshheading:15788406-Binding Sites,
pubmed-meshheading:15788406-Choline-Phosphate Cytidylyltransferase,
pubmed-meshheading:15788406-DNA, Complementary,
pubmed-meshheading:15788406-Epithelial Cells,
pubmed-meshheading:15788406-Extracellular Signal-Regulated MAP Kinases,
pubmed-meshheading:15788406-Flavonoids,
pubmed-meshheading:15788406-Genes, Dominant,
pubmed-meshheading:15788406-Immunoblotting,
pubmed-meshheading:15788406-Immunoprecipitation,
pubmed-meshheading:15788406-Lung,
pubmed-meshheading:15788406-Mice,
pubmed-meshheading:15788406-Mitogen-Activated Protein Kinase 1,
pubmed-meshheading:15788406-Mutagenesis,
pubmed-meshheading:15788406-Mutagenesis, Site-Directed,
pubmed-meshheading:15788406-Mutation,
pubmed-meshheading:15788406-Phosphatidylcholines,
pubmed-meshheading:15788406-Phosphorylation,
pubmed-meshheading:15788406-Proline,
pubmed-meshheading:15788406-Protein Biosynthesis,
pubmed-meshheading:15788406-Protein Structure, Tertiary,
pubmed-meshheading:15788406-Receptors, Steroid,
pubmed-meshheading:15788406-Sterols,
pubmed-meshheading:15788406-Surface-Active Agents,
pubmed-meshheading:15788406-Time Factors,
pubmed-meshheading:15788406-Transcription, Genetic,
pubmed-meshheading:15788406-Transfection,
pubmed-meshheading:15788406-Tretinoin
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pubmed:year |
2005
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pubmed:articleTitle |
Oxysterols inhibit phosphatidylcholine synthesis via ERK docking and phosphorylation of CTP:phosphocholine cytidylyltransferase.
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pubmed:affiliation |
Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City 52242, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, N.I.H., Extramural
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