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Journal of Virology, April 1999, p. 3197-3209, Vol. 73, No. 4
Institute of Microbiology and Immunology,
School of Life Science, National Yang-Ming University, Shih-Pai,
Taipei 11221, Taiwan, Republic of China
Received 22 September 1998/Accepted 17 December 1998
Box
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Transcriptional Repression of Human Hepatitis B
Virus Genes by a bZIP Family Member, E4BP4
is an essential element of both the upstream regulatory
sequence of the core promoter and the second enhancer, which positively
regulate the transcription of human hepatitis B virus (HBV) genes. In
this paper, we describe the cloning and characterization of a box
binding protein, E4BP4. E4BP4 is a bZIP type of transcription factor.
Overexpression of E4BP4 represses the stimulating activity of box
in the upstream regulatory sequence of the core promoter and the second
enhancer in differentiated human hepatoma cell lines. E4BP4 can also
suppress the transcription of HBV genes and the production of HBV
virions in a transient-transfection system that mimics the viral
infection in vivo. Expression of an E4BP4 antisense transcript can,
instead, elevate the transcription of the core promoter. A low
abundance of E4BP4 protein and mRNA in differentiated human hepatoma
cell lines is detected, and E4BP4 is not a major component of box
binding proteins in untransfected differentiated human hepatoma cell
lines. C/EBP
and C/EBP
, in contrast, are major components of the
box
binding activity present in nuclear extracts. E4BP4 has a
stronger binding affinity towards box
than the endogenous box
binding activity present in nuclear extracts. Structure and function
analysis of E4BP4 reveals that DNA binding activity is sufficient to
confer the negative regulatory function of E4BP4. These results
indicate that binding site occlusion is the mechanism whereby E4BP4
suppresses transcription in HBV.
*
Corresponding author. Mailing address: Institute of
Microbiology and Immunology, School of Life Science, National Yang-Ming University, Shih-Pai, Taipei 11221, Taiwan. Phone: 886-2-28222400. Fax:
886-2-28212880. E-mail: lpting{at}ym.edu.tw.
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