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Interference of CREB‐dependent transcriptional activation by expanded polyglutamine stretches – augmentation of transcriptional activation as a potential therapeutic strategy for polyglutamine diseases
Author(s) -
Shimohata M.,
Shimohata T.,
Igarashi S.,
Naruse S.,
Tsuji S.
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2005.03060.x
Subject(s) - creb , creb binding protein , neurodegeneration , microbiology and biotechnology , hdac3 , phosphorylation , transcriptional regulation , biology , activator (genetics) , transcription factor , chemistry , histone , cancer research , histone deacetylase , biochemistry , gene , medicine , disease
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.