Enhanced transcriptional activation by E2 proteins from the oncogenic human papillomaviruses

Kovelman, Robert; Bilter, Graham K.; Glezer, Emilia; Tsou, Amy Y.; Barbosa, Miguel

doi:10.1128/jvi.70.11.7549-7560.1996

Cited by 50 publications

(22 citation statements)

References 60 publications

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“…The HPV16 E6 and E1 plasmids have been previously described (21,27). The p2x2xE2BS-Luc and p16ori plasmids have been previously described (27,66). The pMEP4 HPV16 and HPV31 E2 plasmids have also been previously described (19).…”

Section: Plasmidsmentioning

confidence: 99%

The SMC5/6 Complex Interacts with the Papillomavirus E2 Protein and Influences Maintenance of Viral Episomal DNA

Bentley

Tan

McBride

et al. 2018

J Virol

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The papillomavirus E2 protein executes numerous essential functions related to viral transcription, replication of viral DNA, and viral genome maintenance. Because E2 lacks enzymatic activity, many of these functions are mediated by interactions with host cellular proteins. Unbiased proteomics approaches have successfully identified a number of E2-host protein interactions. We have extended such studies and have identified and validated the cellular proteins SMC5 and SMC6 as interactors of the viral E2 protein. These two proteins make up the core components of the SMC5/6 complex. The SMC5/6 complex is a member of the conserved Structural Maintenance of Chromosomes (SMC) family of proteins, which are essential for genome maintenance. We have examined the role of SMC5/6 in various E2 functions. Our data suggest that SMC6 is not required for E2-mediated transcriptional activation, E1/E2-mediated transient replication, or differentiation-dependent amplification of viral DNA. Our data however suggest a role for SMC5/6 in viral genome maintenance. The high-risk human papillomaviruses are the etiological cause of cervical cancer and the most common sexually transmitted infection. While the majority of infections may be asymptomatic or only cause benign lesions, persistent infection with the oncogenic high-risk HPV types may lead to serious diseases, such as cervical cancer, anogenital carcinoma, or head and neck oropharyngeal squamous cell carcinoma. The identification of virus-host protein interactions provides insights into the mechanisms of viral DNA persistence, viral genome replication, and cellular transformation. Elucidating the mechanism of early events in the virus replication cycle as well as of integration of viral DNA into host chromatin may present novel antiviral strategies and targets for counteracting persistent infection. The E2 protein is an important viral regulatory protein whose functions are mediated through interactions with host cell proteins. Here we explore the interaction of E2 with SMC5/6 and the functional consequences.

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Section: Plasmidsmentioning

confidence: 99%

The SMC5/6 Complex Interacts with the Papillomavirus E2 Protein and Influences Maintenance of Viral Episomal DNA

Bentley

Tan

McBride

et al. 2018

J Virol

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“…Within the HPV-16 long control region (LCR) there are four speci®c E2 recognition sites, characterized by the sequence ACCGN4CGGT, to which E2 binds as a dimer (Androphy et al, 1987a). Through interactions at these sites E2 can speci®cally upregulate the viral oncogene expression (Cripe et al, 1987;Bouvard et al, 1994;Kovelman et al, 1996). Under certain circum-stances, when the E2 protein is overexpressed, transcriptional repression is also observed (Bouvard et al, 1994;Steger and Corbach, 1997).…”

Section: Introductionmentioning

confidence: 99%

Interaction between the HPV-16 E2 transcriptional activator and p53

et al. 1999

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The HPV-16 E2 protein is a major regulator of viral DNA replication and gene expression. Through interactions with the viral origin binding protein, E1, it localizes E1 to the origin of replication and stimulates the initiation of viral DNA replication. However, several recent reports have described a number of diverse activities of E2 relating to the induction of apoptosis through both p53 dependent and independent mechanisms, and to induction of growth arrest in both the G1 and G2M phases of the cell cycle. Recent studies have also shown that p53 can specifically inhibit HPV DNA replication, albeit through an unknown mechanism. Since p53 has been described in the replication centres of Herpes Viruses, Adenovirus and SV40 we decided to investigate whether any of the above activities of E2 may be related to an association with p53. We show, in a series of in vitro assays, specific interaction between p53 and HPV-16 E2 via residues in the carboxy terminal half of the E2 protein. Mutational analysis of p53 indicates that sequences in both the DNA binding and oligomerization domains are essential for the interaction, and a mutant of p53 which is unable to bind E2 is also unable to inhibit HPV DNA replication. Finally, using an inducible system of p53 expression we also show that E2 will complex with p53 in vivo. These results raise the intriguing possibility that p53 may also be involved in HPV DNA replication centres, and also provides explanations for some of the diverse activities reported for the HPV E2 proteins.

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“…In addition, low concentrations of E2 have been suggested to weakly activate P97 transcription through promoter-distal E2 binding sites (9,59). Like the BPV1 E2 protein, HPV E2 proteins can strongly activate transcription from synthetic promoters consisting of multimerized E2 binding sites fused to a minimal promoter (11,29,35,45,50,68).…”

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confidence: 99%

Transactivation by the E2 Protein of Oncogenic Human Papillomavirus Type 31 Is Not Essential for Early and Late Viral Functions

Stubenrauch

Colbert

Laimins

1998

J Virol

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The activation of transcription and of DNA replication are, in some cases, mediated by the same proteins. A prime example is the E2 protein of human papillomaviruses (HPVs), which binds ACCN6GGT sequences and activates heterologous promoters from multimerized binding sites. The E2 protein also has functions in replication, where it complexes with the virally encoded origin recognition protein, E1. Much of the information on these activities is based on transient-transfection assays as well as biochemical analyses; however, their importance in the productive life cycle of oncogenic HPVs remains unclear. To determine the contributions of these E2 functions to the HPV life cycle, a genetic analysis was performed by using an organotypic tissue culture model. HPV type 31 (HPV31) genomes that contained mutations in the N terminus of E2 (amino acid 73) were constructed; these mutants retained replication activities but were transactivation defective. Following transfection of normal human keratinocytes, these mutant genomes were established as stable episomes and expressed early viral transcripts at levels similar to those of wild-type HPV31. Upon differentiation in organotypic raft cultures, the induction of late gene expression and amplification of viral DNA were detected in cell lines harboring mutant genomes. Interestingly, only a modest reduction in late gene expression was observed in the mutant lines. We conclude that the transactivation function of E2 is not essential for the viral life cycle of oncogenic HPVs, although it may act to moderately augment late expression. Our studies suggest that the primary positive role of E2 in the viral life cycle is as a replication factor.

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Enhanced transcriptional activation by E2 proteins from the oncogenic human papillomaviruses

Cited by 50 publications

References 60 publications

The SMC5/6 Complex Interacts with the Papillomavirus E2 Protein and Influences Maintenance of Viral Episomal DNA

The SMC5/6 Complex Interacts with the Papillomavirus E2 Protein and Influences Maintenance of Viral Episomal DNA

Interaction between the HPV-16 E2 transcriptional activator and p53

Transactivation by the E2 Protein of Oncogenic Human Papillomavirus Type 31 Is Not Essential for Early and Late Viral Functions

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