DIFFERENTIAL ACTIVATION OF VIRAL AND CELLULAR PROMOTERS BY HUMAN T-CELL LYMPHOTROPIC VIRUS-1 TAX AND CAMP-RESPONSIVE ELEMENT MODULATOR ISOFORMS

We have previously proposed that cAMP-responsive element-binding prote in (CREB) activity is stimulated by human T-cell lymphotropic virus-1 (HTLV-1) Tax through two mechanisms that are differentially dependent upon CREB phosphorylation. We have tested this model by examining how Tax affects transcriptional activation mediated by the cAMP-responsive element (CRE) modulator (CREM). The CREM proteins are highly homologo us to CREB, particularly in their DNA-binding domains and the kinase-i nducible domain (KID), a region that interacts with the coactivator CR EB-binding protein (CBP) in a phosphorylation-dependent manner. Despit e this similarity, most CREM isoforms are transcriptional repressors. CREM alpha lacks the glutamine-rich domains found in CREB that are ess ential for transcriptional activation. We show that the normally repre ssive CREM alpha activates the HTLV-1 and cellular CREs in the presenc e of Tax; activation of the viral element is phosphorylation-independe nt, and activation of the cellular CRE is phosphorylation-dependent. C REM Delta(C-G) lacks both the KID and the glutamine-rich regions. This isoform activates the HTLV-1 long terminal repeat in a phosphorylatio n-independent manner, but does not activate the cellular CRE. This stu dy suggests that Tax, interacting with the basic/zipper region of CREM , recruits CBP to the viral promoter. Tax activation of the cellular C RE depends on the KID and its ability to interact with CBP in a phosph orylation dependent manner.