title: Altered binding site selection of p53 transcription cassettes by hepatitis B virus X protein.
abstract: The key cellular regulator p53 is a common target of viral oncoproteins. However, the mechanism by which p53 transcription regulation is modulated by hepatitis B virus X protein (HBx), a transcription cofactor implicated in hepatitis B virus-associated hepatocellular carcinoma (HCC), is poorly understood. By integrating p53 chromatin immunoprecipitation (ChIP)-on-chip and expression profiling of an HBx-expressing cell culture system, we report that HBx alters p53 binding site selectivity in the regulatory regions of genes, and this is associated with their aberrant expression. Using an HBx-deregulated gene, p53AIP1, as a model, we show that HBx aberrantly increases p53AIP1 expression by conferring p53 selectivity for a more conserved binding site in its regulatory region. We further demonstrate that HBx-deregulated increased p53AIP1 expression is relevant in HCC livers and define a functional role for p53AIP1 in mediating HBx-induced apoptosis in vitro. Significantly, we provide evidence that specific p53-associated transcription cofactors and coregulators are differentially recruited in the presence of HBx, effecting a PCAF-mediated "p53 Lys320 acetylation switch" that results in altered binding site selection of distinct p53 transcription cassettes. The findings here clarify the role of HBx in modulating p53 transcription regulation and provide a novel mechanistic insight into this deregulation.
authors.affiliation: NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Chan
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Pierce K H
authors.initials: PK
authors.lastname: Chow
authors.forename: Alexander Y F
authors.initials: AY
authors.lastname: Chung
authors.forename: London L P J
authors.initials: LL
authors.lastname: Ooi
authors.forename: Caroline G
authors.initials: CG
authors.lastname: Lee
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006509:Hepatitis B / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D006515:Hepatitis B virus / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D010766:Phosphorylation; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D051017:Apoptosis Regulatory Proteins; C414742:P53AIP1 protein, human; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D004247:DNA