J Virol, March 1998, p. 2113-2124, Vol. 72, No. 3
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Represses Human Papillomavirus Type 18 Upstream Regulatory Region Activity in HeLa Cells by Interfering with
the Binding of TATA-Binding Protein
Forschungsschwerpunkt Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum Heidelberg, 69120 Heidelberg, Germany,1 and Department of Pathology, Harvard Medical School, Boston, Massachusetts 021152
Received 20 August 1997/Accepted 17 November 1997
The human papillomavirus type 18 (HPV-18) upstream regulatory
region (URR) controls cell type-specific expression of viral oncoproteins E6 and E7. The HPV-18 URR is highly active in HeLa cells,
but its activity is virtually undetectable in HepG2 cells. Previous
work has shown that YY1 plays an important role in activation of the
HPV-18 URR in HeLa cells, and this activating activity is dependent on
its physical interaction with C/EBP
, which binds to the switch
region adjacent to the YY1 site in the URR. Overexpression of C/EBP
in HepG2 cells restores C/EBP
-YY1 interaction, resulting in strong
activation of the HPV-18 URR activity. In this report, we show that, in
contrast to the effect in HepG2 cells, overexpression of C/EBP
represses the HPV-18 URR in HeLa cells. This C/EBP
-induced repression of the HPV-18 URR in HeLa cells is binding site independent. It is also promoter specific, since it activates the albumin promoter under conditions in which it represses the URR in the same cells. Biochemical analysis shows that overexpression of C/EBP
in HeLa cells specifically interferes with binding of TATA-binding protein to
the TATA box of the HPV-18 URR, but its overexpression in HepG2 cells
leads to activation of the HPV-18 URR. These results suggest that a
molecular mechanism underlies the ability of C/EBP
to regulate
transcription in a cell type-specific manner and indicate the potential
of using C/EBP
to manipulate the activity of the HPV-18 URR in
cervical carcinoma cells.
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