Regulation of hepatocyte nuclear factor 1 activity by wild-type and mutant hepatitis B virus X proteins.
The hepatitis B virus (HBV) core promoter regulates the transcription of two related RNA products named precore RNA and core RNA. Previous studies indicate that a double-nucleotide mutation that occurs frequently during chronic HBV infection converts a nuclear receptor binding site in the core promoter to the binding site of the transcription factor hepatocyte nuclear factor-1 (HNF-1) and specifically suppresses the transcription of the precore RNA. This mutation also changes two codons in the overlapping X protein coding sequence. In this report, we demonstrate that the X protein and its mutant X(mt) can physically bind to HNF-1 both in vitro and in vivo. Further analyses indicate that both X and X(mt) can enhance the gene transactivation and the DNA binding activities of HNF-1. This finding demonstrates for the first time that the X protein can stimulate the DNA binding activity of a homeodomain transcription factor. Interestingly, while both X and X(mt) can stimulate the HNF-1 activities, they differ in their effects: a smaller amount of X(mt) is needed to generate greater transactivation and DNA binding activities of HNF-1. This functional difference between X and X(mt) may have important implications in HBV pathogenesis and is apparently why they have different effects on the core promoter bearing the HNF-1 binding site.
Li
Jie
J
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
Xu
Zhenming
Z
Zheng
Yanyan
Y
Johnson
Deborah L
DL
Ou
Jing-Hsiung
JH
D001665:Binding Sites; D006528:Carcinoma, Hepatocellular; D004279:DNA, Viral / Q000378:metabolism; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D006515:Hepatitis B virus / Q000235:genetics / Q000378:metabolism; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins; D010957:Plasmids / Q000235:genetics; D011233:Precipitin Tests; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014758:Viral Core Proteins / Q000235:genetics / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins
D004279:DNA, Viral; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D011498:Protein Precursors; D015534:Trans-Activators; D014157:Transcription Factors; D014758:Viral Core Proteins; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta