Source:http://linkedlifedata.com/resource/pubmed/id/21041952
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
12
|
| pubmed:dateCreated |
2010-12-17
|
| pubmed:abstractText |
Noonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, unique facial features, and congenital heart disease. About 10%-15% of individuals with NS have mutations in son of sevenless 1 (SOS1), which encodes a RAS and RAC guanine nucleotide exchange factor (GEF). To understand the role of SOS1 in the pathogenesis of NS, we generated mice with the NS-associated Sos1E846K gain-of-function mutation. Both heterozygous and homozygous mutant mice showed many NS-associated pheno-types, including growth delay, distinctive facial dysmorphia, hematologic abnormalities, and cardiac defects. We found that the Ras/MAPK pathway as well as Rac and Stat3 were activated in the mutant hearts. These data provide in vivo molecular and cellular evidence that Sos1 is a GEF for Rac under physiological conditions and suggest that Rac and Stat3 activation might contribute to NS phenotypes. Furthermore, prenatal administration of a MEK inhibitor ameliorated the embryonic lethality, cardiac defects, and NS features of the homozygous mutant mice, demonstrating that this signaling pathway might represent a promising therapeutic target for NS.
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| pubmed:grant | |
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
AIM
|
| pubmed:chemical | |
| pubmed:status |
MEDLINE
|
| pubmed:month |
Dec
|
| pubmed:issn |
1558-8238
|
| pubmed:author |
pubmed-author:ArakiToshiyukiT,
pubmed-author:BronsonRoderickR,
pubmed-author:ChenPeng-ChiehPC,
pubmed-author:ConnerDavidD,
pubmed-author:KucherlapatiRajuR,
pubmed-author:NeelBenjamin GBG,
pubmed-author:RobertsAmyA,
pubmed-author:SeidmanChristine ECE,
pubmed-author:SeidmanJonathan GJG,
pubmed-author:WakimotoHirokoH,
pubmed-author:YuanTaoT
|
| pubmed:issnType |
Electronic
|
| pubmed:day |
1
|
| pubmed:volume |
120
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
4353-65
|
| pubmed:meshHeading |
pubmed-meshheading:21041952-Animals,
pubmed-meshheading:21041952-Disease Models, Animal,
pubmed-meshheading:21041952-Female,
pubmed-meshheading:21041952-Heart,
pubmed-meshheading:21041952-Heterozygote,
pubmed-meshheading:21041952-Homozygote,
pubmed-meshheading:21041952-Humans,
pubmed-meshheading:21041952-MAP Kinase Signaling System,
pubmed-meshheading:21041952-Male,
pubmed-meshheading:21041952-Mice,
pubmed-meshheading:21041952-Mice, Mutant Strains,
pubmed-meshheading:21041952-Mice, Transgenic,
pubmed-meshheading:21041952-Mutagenesis, Site-Directed,
pubmed-meshheading:21041952-Mutation,
pubmed-meshheading:21041952-Noonan Syndrome,
pubmed-meshheading:21041952-Phenotype,
pubmed-meshheading:21041952-Pregnancy,
pubmed-meshheading:21041952-SOS1 Protein,
pubmed-meshheading:21041952-STAT3 Transcription Factor,
pubmed-meshheading:21041952-Signal Transduction,
pubmed-meshheading:21041952-rac GTP-Binding Proteins
|
| pubmed:year |
2010
|
| pubmed:articleTitle |
Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome–associated Sos1 mutation.
|
| pubmed:affiliation |
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
|
| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
|