Transcriptional activation of human papillomavirus 16 by nuclear factor I, AP1, steroid receptors and a possibly novel transcription factor, PVF: a model for the composition of genital papillomavirus enhancers

Chong, T. C.; Chan, Woon‐Khiong; Bernard, Hans‐Ulrich

doi:10.1093/nar/18.3.465

Cited by 122 publications

(132 citation statements)

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“…The amino acids involved in the recognition of specific DNA sequences, for example, are conserved between bE2 and hE2; the single exception being a bE2 phenylalanine (Phe-343) that is replaced by a tyrosine in the hE2 protein (Tyr-303). The hE2 protein binds to four sites present upstream of the HPV 16 P97 promoter (14). The precise function of the hE2 protein in the regulation of this promoter is the subject of some controversy.…”

mentioning

confidence: 99%

DNA Binding and Bending by the Human Papillomavirus Type 16 E2 Protein

Thain¹,

Webster

Emery³

et al. 1997

Journal of Biological Chemistry

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The human papillomavirus (HPV) 16 E2 protein (hE2) binds to four sites present upstream of the P97 promoter and regulates transcription of the viral E6 and E7 oncogenes. We have determined the relative binding constants for the interaction of the full-length hE2 protein with these sites. Our results show that hE2 binds tightly to site 4, less tightly to sites 1 and 2, and weakly to site 3. Similar results have previously been obtained using a C-terminal fragment of the hE2 protein suggesting that the C-terminal domain is the sole determinant of DNA binding affinity and specificity. Using circular permutation assays we show that binding of the hE2 protein induces the formation of a significant DNA bend and that the hE2-induced DNA bend angle is the same at both tight and weak hE2-binding sites. An alignment of the four hE2-binding sites from the HPV 16 genome suggests that this protein recognizes an extended binding site when compared with the bovine papillomavirus E2 protein. Here we show that the hE2 protein binds tightly to sites containing an A:T or a G:C base pair at position 7 of its binding site but weakly to sites containing either C:G or T:A at this position. Using site-directed mutagenesis we demonstrate that an arginine at position 304 of the hE2 protein is responsible for the recognition of specific base pairs at this position.The recognition of specific DNA sequences by transcription factors is often the first step in the regulation of gene expression. An understanding of how these proteins recognize their target sequences, and the effect that this has on DNA conformation, is central to the question of how genes are controlled. We are studying the human papillomavirus E2 protein, a sequence-specific DNA-binding protein involved in the regulation of viral gene expression and DNA replication. Papillomaviruses infect epithelial cells and induce the formation of benign hyperproliferative lesions or warts. Over 70 distinct types of human papillomavirus (HPV) 1 have been described. Some of these viral types produce lesions that have the potential to undergo malignant transformation. HPV 16 and HPV 18, for example, are thought to play a primary role in the development of cervical cancer (for a review, see Ref. 1). The products of the viral E6 and E7 genes form complexes with the cellular tumor suppressor proteins p53 and Rb, respectively. These interactions bring about a change in cell growth rate and promote cell immortalization (reviewed in Ref.2). In HPV 16, transcription of the E6 and E7 genes is under the control of a single promoter (P97) that lies immediately upstream of the E6 gene (3). The activity of the P97 promoter is regulated by a variety of cellular transcription factors and by the viral E2 protein (4 -6).Much early work concentrated on the bovine papillomavirus (BPV) E2 protein. The BPV E2 protein (bE2) binds as a dimer to 12 inverted repeats (consensus sequence 5Ј-ACCGN 4 CGGT-3Ј) present upstream of the BPV early genes and activates transcription (7,8). Binding of bE2 protein to DNA is coo...

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mentioning

confidence: 99%

DNA Binding and Bending by the Human Papillomavirus Type 16 E2 Protein

Thain¹,

Webster

Emery³

et al. 1997

Journal of Biological Chemistry

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“…It would therefore appear that directing transgene expression to the suprabasal layer may increase the level of transgene expression in the epidermis. The HPV-16 enhancer is known to contain two activator protein 1 (AP1) sites 24 which are thought to play a key role in the differentiation-dependent regulation of viral gene expression. 25 Similarly, the epithelial differentiation markers profilaggrin 26 and involucrin 27 are also considered to be up-regulated by the action of AP1.…”

Section: Figure 5 the Reformed Epidermis Expresses Human Involucrin Amentioning

confidence: 99%

Differentiation-specific enhancer activity in transduced keratinocytes: a model for epidermal gene therapy

Page

Brownlee

1998

Gene Ther

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HaCaT cells, a spontaneously immortalised, nontumoriAfter skin grafting to athymic mice, transduced HaCaT cells genic keratinocyte line, were used as a more amenable differentiated to form a stratified epidermis that remained model than primary keratinocytes for ex vivo-mediated viable for at least 99 days in some mice. Factor IX in gene transfer. These cells were transduced with retroviral plasma of mice grafted with vectors containing the HPVvectors containing the factor IX cDNA under the control of 16 and hK5 elements was two-to three-fold higher than a cytomegaloviral (CMV) promoter/enhancer alone or as with vectors containing the CMV promoter alone. These hybrids with either the human papilloma virus-16 (HPV-16), results are consistent with the expected up-regulation in keratin 14 (hK14) or keratin 5 (hK5) regulatory elements. differentiated suprabasal cells by the HPV-16 and hK5 Unlike primary keratinocytes, HaCaT cells tolerated transelements. Enhancers may be useful in specifically targeting duction and G418 selection well. The HPV-16 and hK5 the differentiated layer of the epidermis or achieving higher hybrid constructs were disproportionately more active in levels of gene expression after transplantation. primary keratinocytes than in the basal-like HaCaT cells.

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“…Between these two regions lies the HPV enhancer, the activity of which depends on cellular nuclear factors (Nakshatri et aL., 1990). ln particular, the HPV-16 and HPV-18 enhancers contain recognition sites for cellular transcription factors such as jun/Jos (Cripe et aL., 1990; Thierry et aL., 1992), nuc1ear factor 1 (NFI), transcription factor Sp l, activator protein APl, glucocorticoid receptor and other papillomavirus enhancer-associated, but not yet characterized, factors (Chong et aL., 1990;Hoppe-Sey1er & Butz, 1992). The activities of individuaI cis-acting elements contribute to the full enhancer activity.…”

Section: (C) Molecular Mechanisms Oftransforming Activity Of Hpvmentioning

confidence: 99%

“…Frequently, recognition sites bind multiple proteins, and individua1 factors can interact with different recognition sequences (Chong et al, 1990;Cripe et aL., 1990;HoppeSeyler & Butz, 1992;Thierry et aL., 1992).…”

Section: (C) Molecular Mechanisms Oftransforming Activity Of Hpvmentioning

confidence: 99%

“…via membrane receptors; or intracelluIar factors that bind the regulatory LCR, either directly or through activation of nuc1ear factors. For exampIe, expression of HPV E6 and E7 can be moduIated by the tumour promoter 12-0-tetradecanoylphorbol 13-acetate, which activates protein kinase C in the plasma membrane, eventually activating the nuc1ear transcription factor APl (Chan et aL., 1990). …”

Section: (C) Molecular Mechanisms Oftransforming Activity Of Hpvmentioning

confidence: 99%

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Monographs on the Evaluation of Carcinogenic Risks to Humans

1991

Analytica Chimica Acta

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Transcriptional activation of human papillomavirus 16 by nuclear factor I, AP1, steroid receptors and a possibly novel transcription factor, PVF: a model for the composition of genital papillomavirus enhancers

Cited by 122 publications

References 24 publications

DNA Binding and Bending by the Human Papillomavirus Type 16 E2 Protein

DNA Binding and Bending by the Human Papillomavirus Type 16 E2 Protein

Differentiation-specific enhancer activity in transduced keratinocytes: a model for epidermal gene therapy

Monographs on the Evaluation of Carcinogenic Risks to Humans

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