Infection with the hepatitis B virus has been identified as one of the major causes of liver cancer. A large body of experimental work points to a central role for the virally encoded protein HBx in this form of carcinogensis. Our discovery that HBx binds to RNA sequences that are AU-rich (1), brought about the question of the specificity of this interaction and whether it is possible to identify and define a sequence binding motif on the mRNAs target for HBx. In order to identify mRNA sequences that can bind to HBx we employed the technique SELEX (Systematic Evolution of Ligands by EXponential enrichment). We were able to identify several potential target RNA sequences that we are currently testing in quantitative and competitive gel-shift experiments. Furthermore, HBx when expressed in HBV-infected liver cells, interacts with a wide range of cellular proteins, thereby interfering in cell signaling, cell cycle regulation and apoptosis (2). In order to identify possible new protein targets of the HBx protein, we performed a yeast two-hybrid screen using a truncated protein mini-HBx (18-142) as bait. In addition to known interacting partners, such as RXR and UVDDB1, we also identified the human transcription factor p120E4F, which has been implicated in the regulation of mitosis and cell cycle (3). The interaction of HBx and E4F was confirmed by pull down experiments in vitro. Further transcription activation assays in the yeast one-hybrid system showed that HBx can repress the expression of a reporter gene under the control of a promotor region containing either E4F binding sites or the HBV enhancer region II. The interaction of HBx and E4F may be of functional importance for cellular transformation and the host-virus co-evolution.