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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
52
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pubmed:dateCreated |
2003-12-22
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pubmed:abstractText |
Surfactant Protein C (SP-C) is a secreted transmembrane protein that is exclusively expressed by alveolar type II epithelial cells of the lung. SP-C associates with surfactant lipids to reduce surface tension within the alveolus, maintaining lung volume at end expiration. Mutations in the gene encoding SP-C (SFTPC) have recently been linked to chronic lung disease in children and adults. The goal of this study was to determine whether a disease-linked mutation in SFTPC causes lung disease in transgenic mice. The SFTPC mutation, designated g.1728 G --> A, results in the deletion of exon4, generating a truncated form of SP-C (SP-C(Deltaexon4)). cDNA encoding SP-C(Deltaexon4) was constitutively expressed in type II epithelial cells of transgenic mice. Viable F0 transgene-positive mice were not generated after two separate rounds of pronuclear injections. Histological analysis of lung tissue harvested from embryonic day 17.5 F0 transgene-positive fetuses revealed that SP-C(Deltaexon4) caused a dose-dependent disruption in branching morphogenesis of the lung associated with epithelial cell cytotoxicity. Transient expression of SP-C(Deltaexon4) in isolated type II epithelial cells or HEK293 cells resulted in incomplete processing of the mutant proprotein, a dose-dependent increase in BiP transcription, trapping of the proprotein in the endoplasmic reticulum, and rapid degradation via a proteasome-dependent pathway. Taken together, these data suggest that the g.1728 G --> A mutation causes misfolding of the SP-C proprotein with subsequent induction of the unfolded protein response and endoplasmic reticulum-associated degradation pathways ultimately resulting in disrupted lung morphogenesis.
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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/Carrier Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/DNA,
http://linkedlifedata.com/resource/pubmed/chemical/DNA, Complementary,
http://linkedlifedata.com/resource/pubmed/chemical/Heat-Shock Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Luciferases,
http://linkedlifedata.com/resource/pubmed/chemical/Molecular Chaperones,
http://linkedlifedata.com/resource/pubmed/chemical/Peptides,
http://linkedlifedata.com/resource/pubmed/chemical/Pulmonary Surfactant-Associated...,
http://linkedlifedata.com/resource/pubmed/chemical/SFTPC protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Sftpc protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/molecular chaperone GRP78
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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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 |
26
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pubmed:volume |
278
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
52739-46
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:14525980-Animals,
pubmed-meshheading:14525980-Blotting, Western,
pubmed-meshheading:14525980-Carrier Proteins,
pubmed-meshheading:14525980-Cell Line,
pubmed-meshheading:14525980-DNA,
pubmed-meshheading:14525980-DNA, Complementary,
pubmed-meshheading:14525980-Dose-Response Relationship, Drug,
pubmed-meshheading:14525980-Endoplasmic Reticulum,
pubmed-meshheading:14525980-Exons,
pubmed-meshheading:14525980-Gene Deletion,
pubmed-meshheading:14525980-Heat-Shock Proteins,
pubmed-meshheading:14525980-Humans,
pubmed-meshheading:14525980-Lipid Metabolism,
pubmed-meshheading:14525980-Luciferases,
pubmed-meshheading:14525980-Lung,
pubmed-meshheading:14525980-Lung Diseases,
pubmed-meshheading:14525980-Mice,
pubmed-meshheading:14525980-Mice, Transgenic,
pubmed-meshheading:14525980-Microscopy, Fluorescence,
pubmed-meshheading:14525980-Models, Genetic,
pubmed-meshheading:14525980-Molecular Chaperones,
pubmed-meshheading:14525980-Mutation,
pubmed-meshheading:14525980-Peptides,
pubmed-meshheading:14525980-Phenotype,
pubmed-meshheading:14525980-Protein Binding,
pubmed-meshheading:14525980-Protein Folding,
pubmed-meshheading:14525980-Protein Transport,
pubmed-meshheading:14525980-Pulmonary Surfactant-Associated Protein C,
pubmed-meshheading:14525980-Time Factors,
pubmed-meshheading:14525980-Transcription, Genetic,
pubmed-meshheading:14525980-Transfection,
pubmed-meshheading:14525980-Transgenes
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pubmed:year |
2003
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pubmed:articleTitle |
Expression of a human surfactant protein C mutation associated with interstitial lung disease disrupts lung development in transgenic mice.
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pubmed:affiliation |
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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