Deacetylase Inhibitors and the Viral Transactivator TaxBLV Synergistically Activate Bovine Leukemia Virus Gene Expression via a cAMP-responsive Element- and cAMP-responsive Element-binding Protein-dependent Mechanism

Efficient bovine leukemia virus (BLV) transcription requires the virus-encoded transactivator Tax BLV , which acts through three Tax BLV -responsive elements located in the 5′ long terminal repeat. It has been proposed that the binding of the CRE-binding protein (CREB) and the activating transcription factor (ATF) to the three imperfect cAMP-responsive elements (CREs) located in each Tax BLV -responsive element mediates Tax BLV transactivation. Here we demonstrated that deacetylase inhibitors (HDACis) synergistically enhanced the transcriptional activation of the BLV promoter by Tax BLV in a CRE-dependent manner. Tax BLV was acetylated in vivo at its N α terminus but not at internal lysine residues. Rather, HDACi potentiation of Tax BLV transactivation was mediated by an HDACi indirect action that requires new protein synthesis. Mechanistically, using a dominant-negative form of CREB, we showed that Tax BLV and HDACi synergistically activated BLV gene expression via a CREB-dependent mechanism. Moreover, electrophoretic mobility shift assay and Western blot experiments revealed that HDACi increased the in vitro DNA binding activity of CREB/ATF but did not alter CREB/ATF intranuclear presence. Remarkably, chromatin immunoprecipitation assays demonstrated that HDACi treatment increased the level of CREB bound to the BLV promoter in vivo . Our results together suggest that an increase in CREB/ATF occupancy of the viral CREs in response to HDACi potentiates Tax BLV transactivation of the BLV promoter.