CREB activation via phosphorylation at serine 133 and resulting CREB mediated gene expression is a critical event which can have a significant effect on many cellular processes, including cell Survival and plasticity. CREB can be activated by many kinases, for example, it can be phosphorylated by PKA, MAPK, and CaMKIV. The Various Signaling pathways leading to CREB activation have been extensively studied. Oil the other hand, CREB is inactivated by Pill through dephosphorylation at S133 and not much attention has been paid to this aspect of the signaling pathway. It was shown recently that PP1 can be targeted to CREB, for efficient dephosphorylation, through PP1 binding protein HDAC1. In this study, we found that another class-I HDAC family protein, HDAC8, localized in the nucleus of HEK293 cells and also bound to both CREB and PP1. Expression of recombinant HDAC8 results in decreased CREB activation and CREB mediated gene transcription in response to forskolin application. Our study thus elucidated that more than one class-I HDAC family members can regulate the duration of CREB mediated gene transcription. (C) 2008 Elsevier Inc. All rights reserved.