Transcriptional Regulation of the Bovine Leukemia Virus Promoter by the Cyclic AMP-response Element Modulator   Isoform (original) (raw)

Bovine leukemia virus (BLV) expression is controlled at the transcriptional level through three Tax BLV-responsive elements (TxREs) responsive to the viral transactivator Tax BLV. The cAMP-responsive element (CRE)-binding protein (CREB) has been shown to interact with CRE-like sequences present in the middle of each of these TxREs and to play critical transcriptional roles in both basal and Tax BLV-transactivated BLV promoter activity. In this study, we have investigated the potential involvement of the cAMP-response element modulator (CREM) in BLV transcriptional regulation, and we have demonstrated that CREM proteins were expressed in BLV-infected cells and bound to the three BLV TxREs in vitro. Chromatin immunoprecipitation assays using BLV-infected cell lines demonstrated in the context of chromatin that CREM proteins were recruited to the BLV promoter TxRE region in vivo. Functional studies, in the absence of Tax BLV , indicated that ectopic CREM protein had a CRE-dependent stimulatory effect on BLV promoter transcriptional activity. Cross-link of the B-cell receptor potentiated CREM transactivation of the viral promoter. Further experiments supported the notion that this potentiation involved CREM Ser-117 phosphorylation and recruitment of CBP/p300 to the BLV promoter. Although CREB and Tax BLV synergistically transactivated the BLV promoter, CREM repressed this Tax BLV /CREB synergism, suggesting that a modulation of the level of Tax BLV transactivation through opposite actions of CREB and CREM could facilitate immune escape and allow tumor development.