P53 BINDS AND REPRESSES THE HBV ENHANCER - AN ADJACENT ENHANCER ELEMENT CAN REVERSE THE TRANSCRIPTION EFFECT OF P53

The transcription program of the hepatitis B virus (HBV) genome is reg ulated by an enhancer element that binds multiple ubiquitous and liver -enriched transcription activators, HBV transcription and replication are repressed in the presence of p53, Here we describe a novel molecul ar mechanism that is responsible for this repression, The p53 protein binds to a defined region within the HBV enhancer in a sequence-specif ic manner, and this, surprisingly, results in p53-dependent transcript ional repression in the context of the whole HBV enhancer, This unusua l behavior of the HBV enhancer can be reconstituted by replacing its p 53-binding region with the p53-binding domain of the mdm2 promoter, Re markably, mutation of the EP element of the enhancer reversed the effe ct of p53 from repression to transcriptional stimulation, Furthermore, EP-dependent modulation of p53 activity can be demonstrated in the co ntext of the mdm2 promoter, suggesting that EP is not only required bu t is also sufficient to convert p53 activity from positive to negative . Our results imply that the transcriptional effect of DNA-bound p53 c an be dramatically modulated by the DNA context and by adjacent DNA-pr otein interactions.