Linked Life Data

16308321

Source:http://linkedlifedata.com/resource/pubmed/id/16308321

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2006-1-30
pubmed:abstractText
Tau exon 10 splicing is altered by autosomal dominant mutations that cause frontotemporal dementia with parkinsonism chromosome 17-type and by unknown mechanisms in other related neurodegenerative disorders. Identifying cis- and trans-regulators of tau exon 10 splicing is therefore crucial for understanding disease mechanisms. We previously identified several splicing enhancers and silencers within exon 10 and intron 10. Here, we show that splicing factors SF2/ASF, Tra2beta, and a 50-kDa nuclear protein bind in vitro to the polypurine enhancer at the 5' end of exon 10. Disease splicing mutations N279K and Delta280K disrupt the enhancer and alter associations with these factors. N279K targets robustly bind Tra2beta compared with the normal enhancer, which may explain why N279K enhances exon 10 splicing in vivo. In contrast, factor associations with Delta280K targets are nearly undetectable, explaining why Delta280K almost abolishes exon 10 splicing in vivo. Small interfering RNA-mediated suppression of endogenous SF2/ASF and Tra2beta significantly reduces exon 10 splicing. Exogenous SF2/ASF dramatically enhances normal exon 10 splicing and efficiently rescues the Delta280K splicing defect. Domain deletion analyses show that the C-terminal RS domains of SF2/ASF and Tra2beta are required for normal exon 10 splicing in vivo. In contrast to Tra2beta, the SF2/ASF RS domain remains essential in the presence of a strengthened enhancer or when either weak splice site is strengthened. The data suggest that SF2/ASF has both essential and regulatory roles, whereas Tra2beta has a supporting role in exon 10 splicing.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
3
pubmed:volume
281
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2460-9
pubmed:dateRevised
2011-9-27
pubmed:meshHeading
pubmed-meshheading:16308321-Alternative Splicing, pubmed-meshheading:16308321-Animals, pubmed-meshheading:16308321-Arginine, pubmed-meshheading:16308321-Binding Sites, pubmed-meshheading:16308321-Enhancer Elements, Genetic, pubmed-meshheading:16308321-Exons, pubmed-meshheading:16308321-HeLa Cells, pubmed-meshheading:16308321-Humans, pubmed-meshheading:16308321-Mutation, pubmed-meshheading:16308321-Neurodegenerative Diseases, pubmed-meshheading:16308321-Nuclear Proteins, pubmed-meshheading:16308321-PC12 Cells, pubmed-meshheading:16308321-Protein Binding, pubmed-meshheading:16308321-RNA Splice Sites, pubmed-meshheading:16308321-RNA-Binding Proteins, pubmed-meshheading:16308321-Rats, pubmed-meshheading:16308321-Ribonucleoproteins, pubmed-meshheading:16308321-Serine, pubmed-meshheading:16308321-tau Proteins
pubmed:year
2006
pubmed:articleTitle
Arginine/serine-rich protein interaction domain-dependent modulation of a tau exon 10 splicing enhancer: altered interactions and mechanisms for functionally antagonistic FTDP-17 mutations Delta280K AND N279K.
pubmed:affiliation
Department of Medicine (Division of Gerontology and Geriatric Medicine), Pharmacology and Neurology, University of Washington, Seattle, Washington 98195, USA. iands@u.washington.edu
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural