Abstract
The transcriptional regulation of the human telomerase reverse transcriptase (hTERT) gene is a critical step in transformation and differentiation. Human papillomavirus E2 protein inhibits cell growth in HPV-infected cells and triggers apoptosis in HeLa cells. Because E2 induces cell growth suppression and senescence, we hypothesize that the protein may modulate cellular gene expression related to these processes. In this report, we demonstrate that E2 inhibits the hTERT promoter. The mapping of the E2-responsive region of hTERT reveals that Sp1 is important for E2-mediated repression of this promoter in 293T cells. Site-directed mutagenesis data on the hTERT promoter show that E2 does not abolish E-Box-mediated transcription and represses promoter activity via the Sp1 binding site. Furthermore, chromatin immunoprecipitation assays indicate that E2 is actively recruited to the hTERT promoter region. Our findings provide novel insights into the biological function of human papillomavirus E2.
Highlights
Papillomavirus (PV),1 which infects mammalian cells, encodes two transcription/replication regulatory proteins (E1 and E2) in its ϳ7900-bp genome [1]
Because the catalytic subunit of telomerase is a primary target for activity and its gene expression is mainly regulated at the transcriptional level, we examined whether human telomerase reverse transcriptase (hTERT) promoter activity was regulated by E2
HPV E2 suppresses the expression of E6 and E7 in HeLa cells, which in turn leads to cell growth arrest [22, 25]
Summary
Vol 277, No 31, Issue of August 2, pp. 27748 –27756, 2002 Printed in U.S.A. Human Papillomavirus E2 Down-regulates the Human Telomerase Reverse Transcriptase Promoter*. The transcriptional regulation of the human telomerase reverse transcriptase (hTERT) gene is a critical step in transformation and differentiation. Papillomavirus (PV), which infects mammalian cells, encodes two transcription/replication regulatory proteins (E1 and E2) in its ϳ7900-bp genome [1]. Both E1 and E2 associate with host cellular proteins involved in the transcriptional regulation and DNA replication, making PV a useful model for the study of these cellular processes in mammals [2,3,4,5]. Telomerase activity is mainly regulated by human telomerase reverse transcriptase (hTERT) gene expression (30 –33). The observation that the introduction of viral E2 into HPV-infected cells inhibits telomerase activity raises the possibility of a link between hTERT expression and the E2 protein. Sp1 sites within the hTERT promoter are important for negative regulation of the HPV E2 protein
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