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.