|CREB-binding protein sequestration by expanded polyglutamine.|
|PMID: 10958659 Owner: NLM Status: MEDLINE|
|Spinal and bulbar muscular atrophy (SBMA) is one of eight inherited neurodegenerative diseases known to be caused by CAG repeat expansion. The expansion results in an expanded polyglutamine tract, which likely confers a novel, toxic function to the affected protein. Cell culture and transgenic mouse studies have implicated the nucleus as a site for pathogenesis, suggesting that a critical nuclear factor or process is disrupted by the polyglutamine expansion. In this report we present evidence that CREB-binding protein (CBP), a transcriptional co-activator that orchestrates nuclear response to a variety of cell signaling cascades, is incorporated into nuclear inclusions formed by polyglutamine-containing proteins in cultured cells, transgenic mice and tissue from patients with SBMA. We also show CBP incorporation into nuclear inclusions formed in a cell culture model of another polyglutamine disease, spinocerebellar ataxia type 3. We present evidence that soluble levels of CBP are reduced in cells expressing expanded polyglutamine despite increased levels of CBP mRNA. Finally, we demonstrate that over-expression of CBP rescues cells from polyglutamine-mediated toxicity in neuronal cell culture. These data support a CBP-sequestration model of polyglutamine expansion disease.|
|A McCampbell; J P Taylor; A A Taye; J Robitschek; M Li; J Walcott; D Merry; Y Chai; H Paulson; G Sobue; K H Fischbeck|
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|Type: Journal Article; Research Support, U.S. Gov't, P.H.S.|
|Title: Human molecular genetics Volume: 9 ISSN: 0964-6906 ISO Abbreviation: Hum. Mol. Genet. Publication Date: 2000 Sep|
|Created Date: 2000-09-29 Completed Date: 2000-11-21 Revised Date: 2009-11-19|
Medline Journal Info:
|Nlm Unique ID: 9208958 Medline TA: Hum Mol Genet Country: ENGLAND|
|Languages: eng Pagination: 2197-202 Citation Subset: IM|
|Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, Building 10, Room 3B11, Bethesda, MD 20892-1250, USA. firstname.lastname@example.org|
|APA/MLA Format Download EndNote Download BibTex|
Cell Death / drug effects
Cell Nucleus / metabolism
Fungal Proteins / metabolism
Green Fluorescent Proteins
Luciferases / metabolism
Luminescent Proteins / metabolism
Machado-Joseph Disease / genetics, metabolism
Muscular Atrophy, Spinal / genetics, metabolism
Nerve Tissue Proteins / metabolism
Nuclear Proteins / metabolism*
Peptides / metabolism*, pharmacology
RNA, Messenger / metabolism
Saccharomyces cerevisiae Proteins*
Scrotum / metabolism
Tetrazolium Salts / pharmacology
Thiazoles / pharmacology
Trans-Activators / metabolism*
Transcription Factors / metabolism
Trinucleotide Repeat Expansion*
|0/CREBBP protein, human; 0/Crebbp protein, mouse; 0/DNA-Binding Proteins; 0/Fungal Proteins; 0/GAL4 protein, S cerevisiae; 0/Luminescent Proteins; 0/Mjd protein, mouse; 0/Nerve Tissue Proteins; 0/Nuclear Proteins; 0/Peptides; 0/RNA, Messenger; 0/Repressor Proteins; 0/Saccharomyces cerevisiae Proteins; 0/Tetrazolium Salts; 0/Thiazoles; 0/Trans-Activators; 0/Transcription Factors; 147336-22-9/Green Fluorescent Proteins; 26700-71-0/polyglutamine; 298-93-1/thiazolyl blue; EC 1.13.12.-/Luciferases; EC 184.108.40.206/CREB-Binding Protein; EC 3.4.22.-/ATXN3 protein, human|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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