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- Title
Interference of CREB-dependent transcriptional activation by expanded polyglutamine stretches– augmentation of transcriptional activation as a potential therapeutic strategy for polyglutamine diseases.
- Authors
Shimohata, M.; Shimohata, T.; Igarashi, S.; Naruse, S.; Tsuji, S.
- Abstract
On the basis of the hypothesis that the interaction of mutant proteins with expanded polyglutamine stretches with transcriptional co-activator, TAFII130, leads to transcriptional dysregulation, the transcriptional activation of c-Fos and its suppression by expanded polyglutamine stretches was investigated. The phosphorylation of cAMP-responsive element binding protein (CREB) and induction of c-Fos in response to cAMP were strongly suppressed in Neuro2a cells expressing expanded polyglutamine. The suppression of CREB-dependent transcriptional activation was reversibly rescued by increasing the concentration of cAMP. Expanded polyglutamine-induced cytotoxicity was also substantially suppressed by augmenting CREB-dependent transcriptional activation with a high concentration of cAMP. FR901228, a histone deacetylase inhibitor, was also demonstrated as rescuing the expanded polyglutamine-induced suppression of CREB phosphorylation and c-Fos expression. Furthermore, nuclear fragmentation was significantly suppressed by FR901228. The co-expression of dominant-negative CREB vectors considerably abrogated the suppressive effect of cAMP and FR901228 on the expanded polyglutamine-induced nuclear fragmentation, suggesting that these compounds suppress polyglutamine-induced cytotoxicity, largely, via the enhancement of CREB-dependent transcriptional activation. These findings suggest that the interference of CREB-dependent transcriptional activation by expanded polyglutamine stretches is involved in the pathogenetic mechanisms underlying neurodegeneration, and that the augmentation of CREB-dependent transcriptional activation is a potential strategy in treating polyglutamine diseases.
- Subjects
GLUTAMINE; CYCLIC adenylic acid; HISTONE deacetylase; NUCLEAR fragmentation; CARRIER proteins; NEUROCHEMISTRY
- Publication
Journal of Neurochemistry, 2005, Vol 93, Issue 3, p654
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/j.1471-4159.2005.03060.x