Interference of CREB-dependent transcriptional activation by expanded polyglutamine stretches--augmentation of transcriptional activation as a potential therapeutic strategy for polyglutamine diseases.
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.
Shimohata
M
M
Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan. m-shimohata@pop17.odn.ne.jp
Shimohata
T
T
Igarashi
S
S
Naruse
S
S
Tsuji
S
S
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis* / Q000235:genetics; D047630:Depsipeptides / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods; D051379:Mice; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*
D017362:Cyclic AMP Response Element-Binding Protein; D047630:Depsipeptides; D010455:Peptides; C097188:polyglutamine; C087123:romidepsin