Shope papillomavirus transcription in benign and malignant rabbit tumors

Phelps, William C.; Leary, Steven L.; Faras, Anthony J.

doi:10.1016/0042-6822(85)90058-3

Cited by 25 publications

(17 citation statements)

References 19 publications

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“…At the moment no assignment of the two transcripts to any of the two integrated DNA segments (A and B) capable of generating them can be made. In rabbit carcinomas two transcripts hybridizing with the E6, E7 and E l ORFs have been reported [4,36,37,41,421. In in vitro transformations other ORF viral transcripts have been detected [40].…”

Section: Discussionmentioning

confidence: 99%

Structure, DNasel hypersensitivity and expression of integrated papilloma virus in the genome of HeLa cells

Lazo

1987

European Journal of Biochemistry

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Three integrated copies of human papilloma virus-18 (HPV-18) have been identified in HeLa DNA as Hind111 bands. HPV-18 has no Hind111 restriction site in its genome. The three segments: A, 8.4 kb; B, 7.9 kb and C, 5.8 kb, have an incomplete viral genome. All of them have most of the 1.1-kb BumHl non-coding fragment of HPV-18, which seems to contain the viral origin of replication and regulatory elements. Two of the segments (A and B) have a common 5'-end break-point in the viral genome within the L2 open reading frame (ORF). In both segments the second early transcriptional unit of the virus (E6, E7 and El) is structurally conserved in a new environment. The 3'-end break-point for segments A and B is within the E2 ORF. Segment C has the L2 and L1 ORF but none of the genes of the early region. Segments A and B have a specific DNaseI-hypersensitive site located in the E7/E1 region. The nucleotide sequence of this region has twelve papova virus enhancer-like consensus sequence (5'-TCCACANA-3') and a double inverted repeat with fixed spacing capable of forming a hairpin loop. Two viral RNA transcripts of 4.8 kb and 1.7 kb have been detected in poly(A)-rich RNA. The larger transcripts hybridizes to E6, E7 and El ORFs as well and has 2.4 kb of host sequence in its 3' end. The smaller transcript hybridizes with E6 and E7 ORFs and the beginnig of El, the final 0.7 kb of El are not detectable. No transcripts have been detected carrying E2, E4, E5, L2 and L1 ORF sequences. The transcripts are derived from segments A or B. Segment C is not transcriptionally competent.A T Papilloma viruses are members of the papova virus family but have not received as much attention as other members of this group (simian virus 40, polyoma), because originally they were not associated with any cancer and were difficult to propagate in cell culture. The better-characterized morphological alterations induced by these viruses are papillomas or fibropapillomas (common warts), an abnormal cellular proliferation in the stratified epithelia [l, 21. More recent information has demonstrated a close association between the presence of this virus and malignant growth in the same area. The best-characterized association was detected in cervical carcinomas in rabbits [3, 41 and more recently in humans Papilloma viruses can infect a wide variety of mammals in a species-specific manner [l]. Many viral types have been identified so far and in spite of their high variation at the nucleotide level their gene organization (Fig. 1) is remarkably conserved (for recent review see [17]). These viruses have circular DNA molecules of approximately 7.5 -8.5 kb. They contain a region considered regulatory and an origin of replication [18], also called the non-coding region or long control region, followed by an early region consisting of eight open reading frames (ORF) and a late region with two ORFs [ll, 19-22]. The best-characterized virus of this family is bovine papilloma virus 1, BPV-1 [22]. Most of the studies [5-161.

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Section: Discussionmentioning

confidence: 99%

Structure, DNasel hypersensitivity and expression of integrated papilloma virus in the genome of HeLa cells

Lazo

1987

European Journal of Biochemistry

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“…Electron microscopic heteroduplex analyses (Croissant et al 1982;Beaudenon et al 1986;Broker and Chow 1986;Chow et al 1987c;Krubke et al 1987) and nucleotide sequence comparisons reveal that all papillomaviruses have similar genetic organization despite substantial nucleotide sequence divergence (Baker 1987). Consistent with this genetic homology, mRNAs of HPV-16, -1, -6, and-11 recovered from cervical carcinomas, plantar warts, and condylomata acuminata, respectively (Smotkin and Wettstein 1986;Chow et al 1987a, b;Nasseri et al 1987), and HPV-16 mRNAs from transformed mouse cells (Yasumoto et al 1987) are rather similar to those of bovine papillomavirus type 1 (BPV-1) present in fibropapillomas and in transformed mouse cells (Stenlund et al 1985;Yang et al 1985; and to those of cottontail rabbit papillomavirus in tumors (Nasseri and Wettstein 1984;Danos et al 1985;Phelps et al 1985). Production of viral messages relies upon alternative usage of promoters, mRNA splice sites, and polyadenylation sites for accessing the various open reading frames (ORFs) deduced from the DNA sequences.…”

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Functional mapping of the human papillomavirus type 11 transcriptional enhancer and its interaction with the trans-acting E2 proteins.

Hirochika

Hirochika²,

Broker³

et al. 1988

Genes Dev.

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The transcriptional enhancer sequences of the papillomaviruses are regulated by trans-acting factors encoded by the viral E2 open reading frame. We have performed detailed functional and physical analyses of the enhancer of the human papillomavirus type 11 (HPV-11). Using the chloramphenicol acetyhransferase (CAT) assay in transiently transfected monkey CV-1 cells, the enhancer region has been localized to a 270-bp tract immediately preceding the E6 open reading frame, and it consists of two functional components. The first is a constitutive enhancer containing sequences homologous to the GT-, Sph-, and P-motifs found in the SV40 and polyomavirus enhancers; others resemble the recognition sequence for CTF (NF-1), a factor which stimulates transcription of certain eukaryotic genes and replication of adenovirus DNA. The second component is an inducible enhancer with a consensus sequence ACCN6GGT responsive to the E2 protein encoded by papillomaviruses. Tandem copies of portions of the constitutive enhancer function as an E2-independent enhancer, whereas multiple copies of HPV-11 DNA restriction fragments or synthetic oligonucleotides containing the E2-responsive sequence (E2-RS) act as an enhancer in the presence of the E2 protein encoded by HPV-1, HPV-11, or bovine papillomavirus type 1 (BPV-1). The inducible activity is lost when mutations are introduced into the E2-RS or when a mutant palindromic sequence is substituted. We have also expressed the E2 proteins of HPV-1, HPV-11, and BPV-1 in Escherichia coli and studied their physical interactions with the E2-responsive sequence in vitro. Filter-binding analyses with crude Escherichia coli lysates show that the E2 proteins bind to the E2-RS, but not to mutated motifs, with an affinity proportional to the copy number. These E2 proteins have been purified to near-homogeneity by sequence-specific DNA affinity chromatography using the synthetic E2-RS as a ligand. The purified proteins protect a DNA segment containing the E2-RS and several flanking nucleotides in pancreatic DNase I footprinting analyses. Based on these results, we conclude that E2 proteins activate the enhancer by binding directly to the E2-RS and interacting with other transcriptional factors and that the sequence ACCN6GGT is both necessary and sufficient for the E2 protein binding in vitro and for activation of RNA transcription in vivo.

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“…In contrast, tissue culture experiments have demonstrated that expression of CRPV LE6 and E7 is sufficient to induce anchorage-independent growth of NIH 3T3 cells and to induce tumors in nude mice injected with the respective cell lines (25). When viral transcripts from benign and malignant tumors were compared by a number of different techniques, no major quantitative or qualitative differences that would have been indicative of a prominent role of a single viral gene product could be observed (27,29,48).A master regulator of early gene expression and viral DNA replication is the multifunctional E2 protein of papillomaviruses. The E2 protein forms dimers that specifically bind to the palindromic DNA sequence ACCN 6 GGT, which can be found in multiple copies in the upstream regions of early and late promoters of papillomaviruses (24).…”

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A Transactivator Function of Cottontail Rabbit Papillomavirus E2 Is Essential for Tumor Induction in Rabbits

Jeckel

Huber

Stubenrauch

et al. 2002

J Virol

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Infection of domestic rabbits with cottontail rabbit papillomavirus (CRPV) causes local papillomas which progress to carcinomas in more than 80% of cases. This animal model system therefore allows the identification of molecular mechanisms required for the induction and progression of epithelial tumors. The viral E2 protein stimulates both viral DNA replication and transcription, and these functions can be genetically separated. We introduced the respective mutations into CRPV E2 and found, in line with published data for other papillomavirus E2 proteins, that mutation of the highly conserved amino acid 37 or 73 resulted in replicationcompetent but transactivation-deficient E2 proteins, whereas E2 proteins with mutations at residue 39 were replication deficient and transactivation competent. The R37A, I73L, and I73A E2 mutants, showing a loss of transactivation function, and the R37K E2 mutant, which is still transactivation competent, were introduced into the whole genome of CRPV, which was then injected into the skin of rabbits. Strikingly, the ability to induce tumors within 6 weeks was abolished by each of the E2 mutations, in contrast to the tumor induction rate (93%) obtained with wild-type CRPV DNA. Two small papillomas induced by mutant E2 I73A CRPV DNA appeared as late as 12 or 24 weeks postinjection, were significantly smaller, and showed no further extension of growth. These data suggest that functionally conserved amino acids in the transactivation domain of E2 are also required for the induction and growth of epithelial tumors in rabbits infected with CRPV. A suitable animal model in which to investigate molecular processes involved in tumor induction and progression by papillomaviruses is the New Zealand White rabbit, which develops local papillomas within 3 to 8 weeks after injection of cottontail rabbit papillomavirus (CRPV) DNA into the skin (45). In contrast to the productive virus infection observed in the cottontail rabbit, which is the natural host, infection of New Zealand White rabbits with CRPV causes an abortive infection (45). As many as 80% of the initially benign epithelial tumors progress to carcinomas within the next 6 to 14 months, and these finally metastasize without the need for cofactors (45). Previous studies using deletion or insertion mutations within the genome have shown that all open reading frames (ORF) of CRPV, except for E5 and L2, are required for tumor induction in rabbits (5,6,25,26,46). In contrast, tissue culture experiments have demonstrated that expression of CRPV LE6 and E7 is sufficient to induce anchorage-independent growth of NIH 3T3 cells and to induce tumors in nude mice injected with the respective cell lines (25). When viral transcripts from benign and malignant tumors were compared by a number of different techniques, no major quantitative or qualitative differences that would have been indicative of a prominent role of a single viral gene product could be observed (27,29,48).A master regulator of early gene expression and viral DNA replication is the m...

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Shope papillomavirus transcription in benign and malignant rabbit tumors

Cited by 25 publications

References 19 publications

Structure, DNasel hypersensitivity and expression of integrated papilloma virus in the genome of HeLa cells

Structure, DNasel hypersensitivity and expression of integrated papilloma virus in the genome of HeLa cells

Functional mapping of the human papillomavirus type 11 transcriptional enhancer and its interaction with the trans-acting E2 proteins.

A Transactivator Function of Cottontail Rabbit Papillomavirus E2 Is Essential for Tumor Induction in Rabbits

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