CREB-binding protein sequestration by expanded polyglutamine

Alexander McCampbell, J. Paul Taylor, Addis A. Taye, Jon Robitschek, Mei Li, Jessica Walcott, Diane Merry, Yaohui Chai, Henry Paulson, Gen Sobue, Kenneth H. Fischbeck

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2197-2202
Number of pages6
JournalHuman molecular genetics
Volume9
Issue number14
StatePublished - Sep 1 2000

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CREB-Binding Protein
Atrophic Muscular Disorders
Intranuclear Inclusion Bodies
Cell Culture Techniques
Transgenic Mice
Machado-Joseph Disease
Poisons
polyglutamine
Neurodegenerative Diseases
Cultured Cells
Proteins
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

McCampbell, A., Taylor, J. P., Taye, A. A., Robitschek, J., Li, M., Walcott, J., ... Fischbeck, K. H. (2000). CREB-binding protein sequestration by expanded polyglutamine. Human molecular genetics, 9(14), 2197-2202.

CREB-binding protein sequestration by expanded polyglutamine. / McCampbell, Alexander; Taylor, J. Paul; Taye, Addis A.; Robitschek, Jon; Li, Mei; Walcott, Jessica; Merry, Diane; Chai, Yaohui; Paulson, Henry; Sobue, Gen; Fischbeck, Kenneth H.

In: Human molecular genetics, Vol. 9, No. 14, 01.09.2000, p. 2197-2202.

Research output: Contribution to journalArticle

McCampbell, A, Taylor, JP, Taye, AA, Robitschek, J, Li, M, Walcott, J, Merry, D, Chai, Y, Paulson, H, Sobue, G & Fischbeck, KH 2000, 'CREB-binding protein sequestration by expanded polyglutamine', Human molecular genetics, vol. 9, no. 14, pp. 2197-2202.
McCampbell A, Taylor JP, Taye AA, Robitschek J, Li M, Walcott J et al. CREB-binding protein sequestration by expanded polyglutamine. Human molecular genetics. 2000 Sep 1;9(14):2197-2202.
McCampbell, Alexander ; Taylor, J. Paul ; Taye, Addis A. ; Robitschek, Jon ; Li, Mei ; Walcott, Jessica ; Merry, Diane ; Chai, Yaohui ; Paulson, Henry ; Sobue, Gen ; Fischbeck, Kenneth H. / CREB-binding protein sequestration by expanded polyglutamine. In: Human molecular genetics. 2000 ; Vol. 9, No. 14. pp. 2197-2202.
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