CHARACTERIZATION OF P53-MEDIATED TRANSCRIPTION DEREGULATION BY THE HEPATITIS B VIRUS X PROTEIN

Abstract

Hepatitis B virus X protein (HBx) is a transcription co-regulator that is strongly implicated in hepatitis B virus-associated hepatocellular carcinoma (HCC). However, how HBx interferes with transcription factors such as p53 remains ill defined. In this thesis, we characterized the modulation of p53-mediated transcription regulation by HBx. We showed that HBx can alter p53 DNA-binding characteristics that are associated with deregulated gene expression. Using p53AIP1 as an example, we found that HBx-induced novel shift in p53-DNA binding directly resulted in aberrantly increased p53AIP1 expression. We showed that this increased p53AIP1 expression by HBx is functionally important and clinically relevant. Further, we demonstrated that HBx altered p53 DNA-binding selectivity by perturbing the recruitment of p53-associated transcription co-regulators and enhancing p53 site-specific acetylation. This work clarifies the role of HBx in detrimentally modulating p53-mediated transcription regulation and provides novel mechanistic insights to this deregulation.