Differential regulation of the pre-C and pregenomic promoters of human hepatitis B virus by members of the nuclear receptor superfamily.
Synthesis of the pre-C and pregenomic RNAs of human hepatitis B virus (HBV) is directed by two overlapping yet separate promoters (X. Yu and J. E. Mertz, J. Virol. 70:8719-8726, 1996). Previously, we reported the identification of a binding site for the nuclear receptor hepatocyte nuclear factor 4 (HNF4) spanning the TATA box-like sequence of the pre-C promoter. This HNF4-binding site consists of an imperfect direct repeat of the consensus half-site sequence 5'-AGGTCA-3' separated by one nucleotide; i.e., it is a DR1 hormone response element (HRE). We show here that other receptors, including chicken ovalbumin upstream promoter transcription factor 1 (COUP-TF1), human testicular receptor 2 (TR2), and peroxisome proliferator-activated receptors (PPARs) as heterodimers with retinoid X receptors (RXRs), can also specifically bind this DR1 HRE. Synthesis of the pre-C and pregenomic RNAs was affected both in transfected hepatoma cells and in a cell-free transcription system by the binding of factors to this DR1 HRE. Interestingly, whereas some members of the hormone receptor superfamily differentially repressed synthesis of the pre-C RNA (e.g., HNF4 and TR2) or activated synthesis of the pregenomic RNA (e.g., PPARgamma-RXRalpha), other members (e.g., COUP-TF1) coordinately repressed synthesis of both the pre-C and pregenomic RNAs. Thus, HBV likely regulates its expression and replication in part via this DR1 HRE. These findings indicate that appropriate ligands to nuclear receptors may be useful in the treatment of HBV infection.
Yu
X
X
McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison 53706-1599, USA.
Mertz
J E
JE
D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051838:COUP Transcription Factor I; D002474:Cell-Free System; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral; D016679:Genome, Viral; D006512:Hepatitis B Core Antigens / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006515:Hepatitis B virus / Q000235:genetics*; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism* / Q000494:pharmacology; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1; D010750:Phosphoproteins / Q000378:metabolism / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D012322:RNA Precursors / Q000096:biosynthesis; D012367:RNA, Viral / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism* / Q000494:pharmacology; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000378:metabolism / Q000494:pharmacology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051838:COUP Transcription Factor I; D004268:DNA-Binding Proteins; D006512:Hepatitis B Core Antigens; D051557:Hepatocyte Nuclear Factor 4; C403128:MLX protein, human; C539822:NR2C1 protein, human; C497589:NR2F1 protein, human; D009687:Nuclear Proteins; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1; D010750:Phosphoproteins; D011498:Protein Precursors; D012322:RNA Precursors; D012367:RNA, Viral; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors