Department of Veterinary and Biomedical Sciences, School of Biological Sciences, University of Nebraska, Lincoln, NE 68583, USA
Correspondence
Clinton Jones
cjones{at}unlnotes.unl.edu
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ABSTRACT |
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INTRODUCTION |
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BHV-1 is a member of the subfamily Alphaherpesvirinae and shares certain biological properties with herpes simplex virus types 1 and 2 (HSV-1 and -2) (Jones, 1998). Viral gene expression is temporally regulated in three distinct phases: immediate early (IE), early (E) or late (L). Two IE transcription units exist: IE transcription unit 1 (IEtu1) and IEtu2. IEtu1 encodes functional homologues of two HSV-1 proteins, ICP0 and ICP4. bICP0 is very important for productive infection because it activates all classes of viral promoters and is expressed at high levels throughout infection (Fraefel et al., 1994
; Wirth et al., 1991
, 1992
).
Most alphaherpesviruses encode an ICP0-like transcription activator that contains a well-conserved C3HC4 zinc ring finger located near the N terminus of these proteins (Everett, 1988, 2000
; Everett et al., 1993
, 1995
; Lium & Silverstein, 1997
). These ICP0 homologues transactivate all classes of viral genes (Bowles et al., 1997
; Fraefel et al., 1994
; Koppel et al., 1996
, 1997
; Lium et al., 1998
) demonstrating they are promiscuous transactivators. Mutational analysis has demonstrated the importance of the zinc ring finger domain in HSV-1 ICP0 (Everett et al., 1993
, 1995
; Everett, 1988
, 2000
; Lium & Silverstein, 1997
), equine herpesvirus-1 ICP0-like protein (Bowles et al., 1997
, 2000
) and BHV-1 bICP0 (Inman et al., 2001b
). ICP0 (Everett et al., 1997
, 1999a
, b
; Maul & Everett, 1994
; Maul et al., 1993
) and bICP0 (Inman et al., 2001b
; Parkinson & Everett, 2000
) colocalize with and disrupt the proto-oncogene promyelocytic leukaemia protein-containing nuclear domains. ICP0 can regulate the stability of cellular and viral proteins by interacting with protein degradation machinery (Everett et al., 1997
, 1999a
). For example, the stability of the catalytic subunit of DNA-dependent protein kinase is regulated by ICP0 (Lees-Miller et al., 1996
; Parkinson et al., 1999
). ICP0 also binds cyclin D3 (Kawaguchi et al., 1997b
) and elongation factor
(Kawaguchi et al., 1997a
). The results of these interactions are perturbation of the cell cycle and altered cellular gene expression (p21, gadd45 and mdm-2, for example) (Hobbs & DeLuca, 1999
). Interestingly, a histone deacetylase inhibitor trichostatin A and ICP0 have similar effects on cellular and viral gene expression (Hobbs & DeLuca, 1999
). bICP0 interacts with histone deacetylase 1, which correlates with activation of gene expression (Zhang & Jones, 2001
). Consequently, regulating chromatin-remodelling enzymes may be an important mechanism by which bICP0 and the other ICP0 homologues regulate virus transcription. Unlike many transactivators of viral gene expression, the ICP0 homologues do not appear to specifically bind to DNA.
In transient transfection assays, BHV-1 DNA yield low numbers of plaques per µg DNA and there is a long latency period prior to plaque formation. Cotransfection of BHV-1 DNA with the gene encoding bICP0 or HSV-1 ICP0 increases the number of plaques and reduces the latency period prior to the appearance of plaques (Geiser et al., 2002; Inman et al., 2001a
, b
). Since bICP0 is a potent transactivator, we assumed that activation of virus transcription was the mechanism for stimulating plaque formation following transfection of cells with viral DNA. These observations also suggested that cellular genes that stimulate virus transcription can substitute for bICP0 or HSV-1 ICP0.
The adenovirus-encoded E1A protein has certain functions that appear to be similar to bICP0. For example, E1A creates a permissive environment for adenovirus productive infection, strongly activates virus transcription, interacts with chromatin-remodelling enzymes but does not directly bind DNA (White, 1998). In addition, E1A (White, 1998
), like bICP0 (Inman et al., 2001b
), is cytotoxic in transiently transfected cells. Although E1A clearly induces apoptosis, it is not clear how bICP0 kills cells. E1A cDNAs encode either a 289 or 243 aa protein that can cooperate with other oncogenes to transform primary baby rat kidney cells (Zerler et al., 1986
). The E1A protein contains several domains that regulate different aspects of the cell cycle, transcription activation and apoptosis. Through mutational analysis, the specific functions of these domains have been identified. Two conserved regions (CR1 and CR2) are required for interaction with p300 and the Rb family of pocket proteins (Rb, p107 and p130) (Stein et al., 1990
; Wang et al., 1993
). Immortalization of mammalian cells by E1A is mediated independently by two regions of the protein that bind p300 and Rb pocket proteins.
The interaction of E1A with a Rb family member leads to the release of bound E2F transcription factors (Harbour & Dean, 2000). In general, E2F proteins that are bound to Rb pocket proteins repress transcription, whereas unbound E2F activates transcription. The association of Rb with histone deacetylases plays an important role in repressing E2F transcription activity. The family of E2F transcription factors interacts with DP (differentiation-regulated transcription factor 1 protein) family members, which are necessary for E2F transcription activation. E2F proteins contain a conserved DNA-binding domain, an acidic transcription activation domain and a Rb-binding site (Harbour & Dean, 2000
). Functional E2F-binding sites are present in the promoters of genes controlling cell cycle progression (DeGregori et al., 1995
; Nevins et al., 1997
; Ohtani et al., 1995
; Schulze et al., 1995
; Wells et al., 1997
). There are several E2F family members and it is clear that these different family members have novel biological properties, in addition to binding consensus E2F-binding sites (Harbour & Dean, 2000
).
In this study, we tested whether non-BHV-1 genes could replace bICP0 and activate productive infection following transfection of bovine cells. The adenovirus E1A gene and E2F-4 gene stimulated productive BHV-1 infection. In contrast, E2F-1, E2F-2 and E2F-5 had little or no effect on productive infection. Since the BHV-1 IEtu1 promoter regulates bICP0 expression, we tested whether the E2F genes could activate IEtu1 promoter activity. E2F-1 and E2F-2 activated IEtu1 promoter activity more than 10-fold in transient transfection assays. In contrast to the IEtu1 promoter, E2F family members did not transactivate the BHV-1 IEtu2 promoter nor an HSV-1 ICP0 promoter construct. In summary, these results implied that distinct E2F family members have the potential to regulate productive infection.
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METHODS |
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BFL cells were transfected with the designated plasmids, as described by the manufacturer, using Superfect (Qiagen). At 16 h prior to transfection, 1·5x105 cells were plated into each well of a 6-well plate or 4·5x105 cells per 60 mm dish. The respective plasmids and viral genomic DNA in the indicated amounts were added together. The total quantity of DNA was adjusted using pcDNA3.1- or pUC19 vector control to 3 µg per well (5 µg per 60 mm dish). The total volume was adjusted to 100 µl (300 µl per 60 mm dish) by adding media without serum or antibiotics followed by 12 µl (20 µl per 60 mm dish) of Superfect. The solution was incubated at room temperature for 10 min and the cells were rinsed with calcium- and magnesium-free PBS (CMF-PBS); 900 µl (1·4 ml per 60 mm dish) of media with serum and antibiotics was then added to the DNA/Superfect solution and this added to the cells. After 3 h at 37 °C, cultures were rinsed three times with CMF-PBS and fresh media added.
Virus.
A BHV-1 mutant containing the -galactosidase (
-Gal) gene in place of the viral gC gene was obtained from S. Chowdury (Manhattan, KS, USA) (gC blue virus). The virus grows to similar titres as the wild-type parent virus and expresses the
-Gal gene.
Extraction of viral genomic DNA.
The procedures for preparing BHV-1 genomic DNA have been described previously (Geiser et al., 2002; Inman et al., 2001a
, b
, 2002
).
-Gal assay.
-Gal activity was measured at 24 or 36 h after transfection, as described previously (Geiser et al., 2002
). The number of
-Gal+ cells in cultures cotransfected with the optimal concentration of bICP0 and viral genomic DNA was set at 100 % infectivity for each experiment. This representation of data minimized the differences in cell density, Superfect lot variation and transfection efficiency.
CAT assays.
Cells were cotransfected with the designated plasmids as indicated. Cells were harvested 48 h after transfection and the levels of CAT were measured as described previously (Delhon & Jones, 1997). After thin layer chromatography, a Phosphorimager (Molecular Dynamics) was used to determine the amount of acetylated or unacetylated [14C]chloramphenicol (CM). The per cent acetylation of cells in the vector control (pcDNA3.1-) was set at 1-fold and the per cent acetylation of each sample was calculated relative to the vector control. This representation of data minimized the differences in cell density, Superfect lot variation and transfection efficiency.
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RESULTS |
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When a bICP0-expressing plasmid was cotransfected with BHV-1 DNA, the number of -Gal+ cells increased approximately 5-fold (Fig. 1A
), which was consistent with our previous studies (Inman et al., 2001b
). When the E1A 12S.WT expression plasmid was cotransfected with BHV-1 DNA, the number of
-Gal+ cells increased more than 3-fold (Fig. 1A
), indicating that the E1A gene activated BHV-1 productive infection.
Several E1A mutants have been constructed to identify domains that regulate cell cycle and gene expression. The 12S.WT plasmid is the wt adenovirus E1A construct that all mutants were derived from. The mutants used in this study are described in Methods and are summarized schematically in Fig. 1(B). To determine what effects these mutations had on stimulating productive infection, the respective E1A mutants were cotransfected with BHV-1 DNA into BFL cells and the number of
-Gal+ cells counted at 36 h after transient transfection. The 12S.RG2 mutant encodes a protein that does not bind p300 or induce p53 expression and which stimulated BHV-1 productive infection with similar efficiency as wt E1A (Fig. 1A
). A mutation at position 47 (12S.YH47) encodes a protein that does not bind Rb and p130 and this mutant stimulated productive infection less efficiently than wt E1A. A mutation at position 928 (12S.928), or in combination with aa 2 (12S.RG2.928) or 47 (12S.YH47.928), also reduced the number of
-Gal+ cells. Although it was clear that none of the mutants completely prevented stimulation of productive infection, these studies suggested that the ability of E1A to bind Rb family members played a role in stimulating productive infection.
E2F-4 stimulates productive infection
The underphosphorylated forms of the Rb family associate with E2F family members to repress proliferation, differentiation and apoptosis in a variety of tissues (Harbour & Dean, 2000). The interaction of E1A with the underphosphorylated forms of the Rb family leads to release of E2F family members. Consequently, we hypothesized that E2F family members may play a role in stimulating BHV-1 productive infection. To measure the effect of E2F on productive infection, increasing amounts of plasmids expressing E2F-1, E2F-2, E2F-4 or E2F-5 were cotransfected with BHV-1 genomic DNA and the number of
-Gal+ cells counted at 36 h after transfection. Cultures transfected with E2F-4 and BHV-1 DNA consistently increased the number of
-Gal+ cells more than 3-fold (Fig. 2
). In contrast, cotransfection of BHV-1 DNA with E2F-1 or E2F-2 yielded similar numbers of
-Gal+ cells as those transfected with just the blank expression vector. E2F-5 increased the number of
-Gal+ cells approximately 2-fold. In summary, this study indicated that E2F-4 consistently stimulated BHV-1 productive infection by 3-fold, which was similar to wt E1A.
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Bax-induced apoptosis does not lead to activation of the BHV IEtu1 promoter
E2F-1 and E2F-2 can induce apoptosis in a variety of cell types (Harbour & Dean, 2000), including BFL cells (data not shown), suggesting that the ability of E2F-1 or E2F-2 to induce apoptosis was responsible for increased IEtu1 promoter activity. E2F-1 and the pro-apoptotic protein Bax can both induce apoptosis via the mitochondrial pathway (reviewed by Wang, 2001
). To test whether activation of the mitochondrial pathway of apoptosis was responsible for stimulating IEtu1 promoter activity, increasing amounts of a Bax expression plasmid were cotransfected with IEtu1cat. Bax-induced apoptosis did not stimulate IEtu1 promoter activity, whereas E2F-1 strongly stimulated IEtu1 promoter activity (Fig. 6
), suggesting that induction of the mitochondrial pathway of apoptosis was not the mechanism by which E2F-1 transactivated IEtu1 promoter activity.
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DISCUSSION |
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Since E2F-4 was the only E2F family member that was capable of consistently activating productive infection, it is reasonable to ask whether E2F-4 has novel properties or functions. E2F-4 lacks a nuclear localization signal (Helin et al., 1992; Kaelin et al., 1992
) and the cyclin A-binding site that is present at the N terminus of other E2F proteins (Harbour & Dean, 2000
). E2F-4 transcription activity is regulated by phosphorylation (Helin et al., 1993
; Tao et al., 1997
), association with other cellular proteins (Weintraub et al., 1992
) and subcellular localization (Allen et al., 1997
; Verona et al., 1997
). E2F-4 can bind to all of the Rb family members but there is a preference for p107 and p130 (Harbour & Dean, 2000
). Ectopic expression of E2F-4 in Chinese hamster cells does not activate E2F-dependent transcription, demonstrating that E2F-4 has novel functions (Chang et al., 2000
). Interestingly, human immunodeficiency virus-encoded Tat specifically interacts with E2F-4 and Tat can stimulate an E2F responsive promoter (Ambrosino et al., 2002
). Since E2F-4 does not directly stimulate IEtu1 promoter activity, we suggest that a virus-specific modification of E2F-4 may occur during productive infection that is necessary for IEtu1 promoter activation or E2F-4 activates productive infection by an independent mechanism.
Our studies have suggested that E2F family members, and perhaps other cell cycle regulators, stimulate BHV-1 productive infection. There are a number of studies that have concluded that cell cycle regulatory proteins play an important role in the early stages of infection. For example, it is clear that cell factors in G1 or S enhance the growth of ICP0- mutants (Cai & Schaffer, 1991) and the ability of VP16 to activate transcription (Daksis & Preston, 1992
). Further support that cell cycle regulatory proteins play a role in productive infection comes from studies demonstrating that a Cdk2 and Cdc2 inhibitor (roscovitine) inhibits HSV-1 infection, in part because IE and E transcription is blocked (Schang et al., 1998
, 1999
). Although it is clear that infection with HSV-1 and presumably BHV-1 leads to cell cycle arrest (reviewed by Flemington, 2001
), specific cell cycle regulatory proteins may stimulate productive infection in certain cell types.
Several studies have demonstrated that E2F function is modified following HSV-1 infection. For example, E2F not bound to Rb family members is increased following infection of human cells (C33-A) (Hilton et al., 1995). Relocalization of E2F-4 to the nucleus occurs in C33-A and U2-OS human cells following infection of HSV-1 (Olgiate et al., 1999
). Further support for E2F-4 playing a role in HSV-1 replication comes from the findings that infection of p107-/-/p130-/- mouse cells leads to reduced titres of infectious virus (Ehmann et al., 2001
). Since E2F-4 is bound to p107 and p130, this implies that E2F-4 plays a role in HSV-1 infection. Another study concluded that HSV-1 infection leads to inactivation of E2F family members. For example, in primary human fibroblasts or HeLa cells, the intracellular levels of E2F-4 are reorganized following HSV-1 infection, but this is assumed to inactivate E2F-4 activity (Advani et al., 2000
). This same study also concluded that HSV-1 infections lead to post-translational modification of E2F-1 and E2F-5, translocation of E2F family members from the nucleus to the cytoplasm and reduced E2F binding to consensus E2F-binding sites. Since many DNA synthetic genes are activated by E2F family members (Harbour & Dean, 2000
), we suggest that transient induction of one or another E2F family member could promote BHV-1 DNA synthesis in highly differentiated cells.
In spite of the fact that the IEtu1 promoter does not contain a consensus E2F-binding site, we believe that specific sequences in the IEtu1 promoter are responsive to E2F-1 and E2F-2. E2F-1 can activate the HSV-1 thymidine kinase promoter (Shin et al., 1996) and the ASK gene that encodes the regulatory subunit for human Cdc7-related kinase (Yamada et al., 2002
), independently of a consensus E2F-binding site. The E2F responsive region of each promoter contains a GC-rich motif that resembles a Sp1-binding site. IEtu1 and IEtu2 promoters each contain numerous GC-rich sequences that resemble Sp1-binding sites, confirming further that activation of the IEtu1 promoter by E2F-1 and E2F-2 requires a novel motif that is only present in the IEtu1 promoter. It will be of interest to identify the specific cis-acting sequences in the IEtu1 promoter that are responsive to E2F-1 and determine what the effects of mutating these sequences have on productive infection and growth in cattle.
The following model is put forth to explain our findings with respect to BHV-1 biology and the potential role that E2F family members play in stimulating productive infection. The ability of E2F-4 to stimulate productive infection is proposed to be independent of activating the IEtu1 promoter. Additional studies are required to identify the step in productive infection that E2F-4 stimulates. Although E2F-1 did not dramatically stimulate BHV-1 productive infection, the ability of E2F-1 to activate the IEtu1 promoter has biological relevance during productive infection and perhaps reactivation from latency because G1 and S phase cyclins are activated in infected neurons during acute infection and reactivation from latency (Winkler et al., 1999). Since cyclin expression correlates with E2F transcription activation (reviewed by Harbour & Dean, 2000
), the ability of BHV-1 to stimulate cyclin expression would lead to free E2F and activation of the IEtu1 promoter. Virion components of alphaherpesviruses can inhibit apoptosis (reviewed by Blaho & Aubert, 2001
), suggesting that, in the context of virus infection, E2F-1 or E2F-2 could activate IEtu1 promoter activity without inducing apoptosis. Finally, this model predicts that BHV-1 productive infection leads to activation of E2F family members.
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ACKNOWLEDGEMENTS |
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REFERENCES |
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Allen, K. E., de la Luna, S., Kerkhoven, R. M., Bernards, R. & La Thangue, N. B. (1997). Distinct mechanisms of nuclear accumulation regulate the functional consequence of E2F transcription factors. J Cell Sci 110, 28192831.
Ambrosino, C., Palmieri, C., Puca, A. & 9 other authors (2002). Physical and functional interaction of HIV tat with E2F-4, a transcriptional regulator of mammalian cell cycle. J Biol Chem 272, 3144831458.[CrossRef]
Blaho, M. & Aubert, J. A. (2001). Modulation of apoptosis during herpes simplex virus infection in human cells. Microbes Infect 3, 18.
Bowland, S. L. & Shewen, P. E. (2000). Bovine respiratory disease: commercial vaccines currently available in Canada. Can Vet J 41, 3348.[Medline]
Bowles, D. E., Holden, V. R., Zhao, Y. & O'Callaghan, D. J. (1997). The ICP0 protein of equine herpesvirus 1 is an early protein that independently transactivates expression of all classes of viral promoters. J Virol 71, 49044914.[Abstract]
Bowles, D. E., Kim, S. K. & O'Callaghan, D. J. (2000). Characterization of the trans-activation properties of equine herpesvirus 1 EICP0 protein. J Virol 74, 12001208.
Cai, W. & Schaffer, P. A. (1991). A cellular function can enhance gene expression and plating efficiency of a mutant defective in the gene for ICP0, a transactivating protein of herpes simplex virus type 1. J Virol 65, 40784090.[Medline]
Carter, J. J., Weinberg, A. D., Pollard, A., Reeves, R., Magnuson, J. A. & Magnuson, N. S. (1989). Inhibition of T-lymphocyte mitogenic responses and effects on cell functions by bovine herpesvirus 1. J Virol 63, 15251530.[Medline]
Chang, Y. C., Nakajima, H., Illenye, S. & 10 other authors (2000). Caspase-dependent apoptosis by ectopic expression of E2F-4. Oncogene 19, 47134720.[CrossRef][Medline]
Daksis, J. I. & Preston, C. M. (1992). Herpes simplex virus immediate early gene expression in the absence of transinduction by Vmw65 varies during the cell cycle. Virology 189, 196202.[Medline]
Dallas, P. B., Pacchione, S., Wilsker, D., Bowrin, V., Kobayashi, R. & Moran, E. (2000). The human SWISNF complex protein p270 is an ARID family member with non-sequence-specific DNA binding activity. Mol Cell Biol 20, 31373146.
DeGregori, J., Kowalik, T. & Nevins, J. R. (1995). Cellular targets for activation by the E2F1 transcription factor include DNA synthesis- and G1/S-regulatory genes. Mol Cell Biol 15, 42154224.[Abstract]
Delhon, G. & Jones, C. (1997). Identification of DNA sequences in the latency related promoter of bovine herpes virus type 1 which are bound by neuronal specific factors. Virus Res 51, 93103.[CrossRef][Medline]
Devireddy, L. R. & Jones, C. J. (2000). Olf-1, a neuron-specific transcription factor, can activate the herpes simplex virus type 1-infected cell protein 0 promoter. J Biol Chem 275, 7781.
Ehmann, G. L., Burnett, H. A. & Bachenheimer, S. L. (2001). Pocket protein p130/Rb2 is required for efficient herpes simplex virus type 1 gene expression and viral replication. J Virol 75, 71497160.
Everett, R. D. (1988). Analysis of the functional domains of herpes simplex virus type 1 immediate-early polypeptide Vmw110. J Mol Biol 202, 8796.[Medline]
Everett, R. D. (2000). ICP0, a regulator of herpes simplex virus during lytic and latent infection. Bioessays 22, 761770.[CrossRef][Medline]
Everett, R. D., Barlow, P., Milner, A., Luisi, B., Orr, A., Hope, G. & Lyon, D. (1993). A novel arrangement of zinc-binding residues and secondary structure in the C3HC4 motif of an alpha herpes virus protein family. J Mol Biol 234, 10381047.[CrossRef][Medline]
Everett, R., O'Hare, P., O'Rourke, D., Barlow, P. & Orr, A. (1995). Point mutations in the herpes simplex virus type 1 Vmw110 RING finger helix affect activation of gene expression, viral growth, and interaction with PML-containing nuclear structures. J Virol 69, 73397344.[Abstract]
Everett, R. D., Meredith, M., Orr, A., Cross, A., Kathoria, M. & Parkinson, J. (1997). A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein. EMBO J 16, 15191530.
Everett, R. D., Earnshaw, W. C., Findlay, J. & Lomonte, P. (1999a). Specific destruction of kinetochore protein CENP-C and disruption of cell division by herpes simplex virus immediate-early protein Vmw110. EMBO J 18, 15261538.
Everett, R. D., Lomonte, P., Sternsdorf, T., van Driel, R. & Orr, A. (1999b). Cell cycle regulation of PML modification and ND10 composition. J Cell Sci 112, 45814588.
Flemington, E. K. (2001). Herpesvirus lytic replication and the cell cycle: arresting new developments. J Virol 75, 44754881.
Fraefel, C., Zeng, J., Choffat, Y., Engels, M., Schwyzer, M. & Ackermann, M. (1994). Identification and zinc dependence of the bovine herpesvirus 1 transactivator protein BICP0. J Virol 68, 31543162.[Abstract]
Geiser, V., Inman, M., Zhang, Y. & Jones, C. (2002). The latency-related gene of bovine herpesvirus-1 can inhibit the ability of bICP0 to activate productive infection. J Gen Virol 83, 29652971.
Griebel, P. J., Qualtiere, L., Davis, W. C., Gee, A., Bielefeldt Ohmann, H., Lawman, M. J. & Babiuk, L. A. (1987a). T lymphocyte population dynamics and function following a primary bovine herpesvirus type-1 infection. Viral Immunol 1, 287304.[Medline]
Griebel, P. J., Qualtiere, L., Davis, W. C., Lawman, M. J. & Babiuk, L. A. (1987b). Bovine peripheral blood leukocyte subpopulation dynamics following a primary bovine herpesvirus-1 infection. Viral Immunol 1, 267286.[Medline]
Griebel, P. J., Ohmann, H. B., Lawman, M. J. & Babiuk, L. A. (1990). The interaction between bovine herpesvirus type 1 and activated bovine T lymphocytes. J Gen Virol 71, 369377.[Abstract]
Harbour, J. W. & Dean, D. C. (2000). The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev 14, 23932409.
Hariharan, M. J., Nataraj, C. & Srikumaran, S. (1993). Down regulation of murine MHC class I expression by bovine herpesvirus 1. Viral Immunol 6, 273284.[Medline]
Helin, K., Lees, J. A., Vidal, M., Dyson, N., Harlow, E. & Fattaey, A. (1992). A cDNA encoding a pRB-binding protein with properties of the transcription factor E2F. Cell 70, 337350.[Medline]
Helin, K., Wu, C. L., Fattaey, A. R., Lees, J. A., Dynlacht, B. D., Ngwu, C. & Harlow, E. (1993). Heterodimerization of the transcription factors E2F-1 and DP-1 leads to cooperative trans-activation. Genes Dev 7, 18501861.[Abstract]
Hilton, M. J., Mounghane, D., McLean, T., Contractor, N. V., O'Neil, J., Carpenter, K. & Bachenheimer, S. L. (1995). Induction by herpes simplex virus of free and heteromeric forms of E2F transcription factor. Virology 213, 624638.[CrossRef][Medline]
Hinkley, S., Hill, A. B. & Srikumaran, S. (1998). Bovine herpesvirus-1 infection affects the peptide transport activity in bovine cells. Virus Res 53, 9196.[CrossRef][Medline]
Hobbs, W. E., II & DeLuca, N. A. (1999). Perturbation of cell cycle progression and cellular gene expression as a function of herpes simplex virus ICP0. J Virol 73, 82458255.
Inman, M., Lovato, L., Doster, A. & Jones, C. (2001a). A mutation in the latency-related gene of bovine herpesvirus 1 leads to impaired ocular shedding in acutely infected calves. J Virol 75, 85078515.
Inman, M., Zhang, Y., Geiser, V. & Jones, C. (2001b). The zinc ring finger in the bICP0 protein encoded by bovine herpesvirus-1 mediates toxicity and activates productive infection. J Gen Virol 82, 483492.
Inman, M., Lovato, L., Doster, A. & Jones, C. (2002). A mutation in the latency-related gene of bovine herpesvirus 1 disrupts the latency reactivation cycle in calves. J Virol 76, 67716779.
Jones, C. (1998). Alphaherpesvirus latency: its role in disease and survival of the virus in nature. Adv Virus Res 51, 81133.[Medline]
Jones, C., Newby, T. J., Holt, T., Doster, A., Stone, M., Ciacci-Zanella, J., Webster, C. J. & Jackwood, M. W. (2000). Analysis of latency in cattle after inoculation with a temperature sensitive mutant of bovine herpesvirus 1 (RLB106). Vaccine 18, 31853195.[CrossRef][Medline]
Kaelin, W. G., Jr, Krek, W., Sellers, W. R. & other authors (1992). Expression cloning of a cDNA encoding a retinoblastoma-binding protein with E2F-like properties. Cell 70, 351364.[Medline]
Kawaguchi, Y., Bruni, R. & Roizman, B. (1997a). Interaction of herpes simplex virus 1 regulatory protein ICP0 with elongation factor 1
: ICP0 affects translational machinery. J Virol 71, 10191024.[Abstract]
Kawaguchi, Y., Van Sant, C. & Roizman, B. (1997b). Herpes simplex virus 1 regulatory protein ICP0 interacts with and stabilizes the cell cycle regulator cyclin D3. J Virol 71, 73287336.[Abstract]
Koppel, R., Fraefel, C., Vogt, B., Bello, L. J., Lawrence, W. C. & Schwyzer, M. (1996). Recombinant bovine herpesvirus-1 (BHV-1) lacking transactivator protein BICP0 entails lack of glycoprotein C and severely reduced infectivity. Biol Chem 377, 787795.[Medline]
Koppel, R., Vogt, B. & Schwyzer, M. (1997). Immediate-early protein BICP22 of bovine herpesvirus 1 trans-represses viral promoters of different kinetic classes and is itself regulated by BICP0 at transcriptional and posttranscriptional levels. Arch Virol 142, 24472464.[CrossRef][Medline]
Lees-Miller, S. P., Long, M. C., Kilvert, M. A., Lam, V., Rice, S. A. & Spencer, C. A. (1996). Attenuation of DNA-dependent protein kinase activity and its catalytic subunit by the herpes simplex virus type 1 transactivator ICP0. J Virol 70, 74717477.[Abstract]
Lium, E. K. & Silverstein, S. (1997). Mutational analysis of the herpes simplex virus type 1 ICP0 C3HC4 zinc ring finger reveals a requirement for ICP0 in the expression of the essential 27 gene. J Virol 71, 86028614.[Abstract]
Lium, E. K., Panagiotidis, C. A., Wen, X. & Silverstein, S. J. (1998). The NH2 terminus of the herpes simplex virus type 1 regulatory protein ICP0 contains a promoter-specific transcription activation domain. J Virol 72, 77857795.
Maul, G. G. & Everett, R. D. (1994). The nuclear location of PML, a cellular member of the C3HC4 zinc-binding domain protein family, is rearranged during herpes simplex virus infection by the C3HC4 viral protein ICP0. J Gen Virol 75, 12231233.[Abstract]
Maul, G. G., Guldner, H. H. & Spivack, J. G. (1993). Modification of discrete nuclear domains induced by herpes simplex virus type 1 immediate early gene 1 product (ICP0). J Gen Virol 74, 26792690.[Abstract]
Misra, V., Bratanich, A. C., Carpenter, D. & O'Hare, P. (1994). Protein and DNA elements involved in transactivation of the promoter of the bovine herpesvirus (BHV) 1 IE-1 transcription unit by the BHV gene trans-inducing factor. J Virol 68, 48984909.[Abstract]
Misra, V., Walker, S., Hayes, S. & O'Hare, P. (1995). The bovine herpesvirus gene trans-inducing factor activates transcription by mechanisms different from those of its herpes simplex virus type 1 counterpart VP16. J Virol 69, 52095216.[Abstract]
Nataraj, C., Eidmann, S., Hariharan, M. J., Sur, J. H., Perry, G. A. & Srikumaran, S. (1997). Bovine herpesvirus 1 downregulates the expression of bovine MHC class I molecules. Viral Immunol 10, 2134.[Medline]
Nevins, J. R., DeGregori, J., Jakoi, L. & Leone, G. (1997). Functional analysis of E2F transcription factor. Methods Enzymol 283, 205219.[CrossRef][Medline]
Ohtani, K., DeGregori, J. & Nevins, J. R. (1995). Regulation of the cyclin E gene by transcription factor E2F1. Proc Natl Acad Sci U S A 92, 1214612150.[Abstract]
Olgiate, J., Ehmann, G. L., Vidyarthi, S., Hilton, M. J. & Bachenheimer, S. L. (1999). Herpes simplex virus induces intracellular redistribution of E2F4 and accumulation of E2F pocket protein complexes. Virology 258, 257270.[CrossRef][Medline]
Parkinson, J. & Everett, R. D. (2000). Alphaherpesvirus proteins related to herpes simplex virus type 1 ICP0 affect cellular structures and proteins. J Virol 74, 1000610017.
Parkinson, J., Lees-Miller, S. P. & Everett, R. D. (1999). Herpes simplex virus type 1 immediate-early protein vmw110 induces the proteasome-dependent degradation of the catalytic subunit of DNA-dependent protein kinase. J Virol 73, 650657.
Schang, L. M., Phillips, J. & Schaffer, P. A. (1998). Requirement for cellular cyclin-dependent kinases in herpes simplex virus replication and transcription. J Virol 72, 56265637.
Schang, L. M., Rosenberg, A. & Schaffer, P. A. (1999). Transcription of herpes simplex virus immediate-early and early genes is inhibited by roscovitine, an inhibitor specific for cellular cyclin-dependent kinases. J Virol 73, 21612172.
Schulze, A., Zerfass, K., Spitkovsky, D., Middendorp, S., Berges, J., Helin, K., Jansen-Durr, P. & Henglein, B. (1995). Cell cycle regulation of the cyclin A gene promoter is mediated by a variant E2F site. Proc Natl Acad Sci U S A 92, 1126411268.[Abstract]
Schwyzer, M., Wirth, U. V., Vogt, B. & Fraefel, C. (1994). BICP22 of bovine herpesvirus 1 is encoded by a spliced 1·7 kb RNA which exhibits immediate early and late transcription kinetics. J Gen Virol 75, 17031711.[Abstract]
Shin, E. K., Tevosian, S. G. & Yee, A. S. (1996). The N-terminal region of E2F-1 is required for transcriptional activation of a new class of target promoter. J Biol Chem 271, 1226112268.
Stein, R. W., Corrigan, M., Yaciuk, P., Whelan, J. & Moran, E. (1990). Analysis of E1A-mediated growth regulation functions: binding of the 300-kilodalton cellular product correlates with E1A enhancer repression function and DNA synthesis-inducing activity. J Virol 64, 44214427.[Medline]
Tao, Y., Kassatly, R. F., Cress, W. D. & Horowitz, J. M. (1997). Subunit composition determines E2F DNA-binding site specificity. Mol Cell Biol 17, 69947007.[Abstract]
Tikoo, S. K., Campos, M. & Babiuk, L. A. (1995). Bovine herpesvirus 1 (BHV-1): biology, pathogenesis, and control. Adv Virus Res 45, 191223.[Medline]
Verona, R., Moberg, K., Estes, S., Starz, M., Vernon, J. P. & Lees, J. A. (1997). E2F activity is regulated by cell cycle-dependent changes in subcellular localization. Mol Cell Biol 17, 72687282.[Abstract]
Wang, X. (2001). The expanding role of mitochondria in apoptosis. Genes Dev. 15, 29222933.
Wang, H. G., Draetta, G. & Moran, E. (1991). E1A induces phosphorylation of the retinoblastoma protein independently of direct physical association between the E1A and retinoblastoma products. Mol Cell Biol 11, 42534265.[Medline]
Wang, H. G., Rikitake, Y., Carter, M. C., Yaciuk, P., Abraham, S. E., Zerler, B. & Moran, E. (1993). Identification of specific adenovirus E1A N-terminal residues critical to the binding of cellular proteins and to the control of cell growth. J Virol 67, 476488.[Abstract]
Weintraub, S. J., Prater, C. A. & Dean, D. C. (1992). Retinoblastoma protein switches the E2F site from positive to negative element. Nature 358, 259261.[CrossRef][Medline]
Wells, J. M., Illenye, S., Magae, J., Wu, C. L. & Heintz, N. H. (1997). Accumulation of E2F-4.DP-1 DNA binding complexes correlates with induction of dhfr gene expression during the G1 to S phase transition. J Biol Chem 272, 44834492.
White, E. (1998). Regulation of apoptosis by adenovirus E1A and E1B oncogenes. Semin Virol 8, 505513.[CrossRef]
Winkler, M. T., Doster, A. & Jones, C. (1999). Bovine herpesvirus 1 can infect CD4+ T lymphocytes and induce programmed cell death during acute infection of cattle. J Virol 73, 86578668.
Wirth, U. V., Gunkel, K., Engels, M. & Schwyzer, M. (1989). Spatial and temporal distribution of bovine herpesvirus 1 transcripts. J Virol 63, 48824889.[Medline]
Wirth, U. V., Vogt, B. & Schwyzer, M. (1991). The three major immediate-early transcripts of bovine herpesvirus 1 arise from two divergent and spliced transcription units. J Virol 65, 195205.[Medline]
Wirth, U. V., Fraefel, C., Vogt, B., Vlcek, C., Paces, V. & Schwyzer, M. (1992). Immediate-early RNA 2.9 and early RNA 2.6 of bovine herpesvirus 1 are 3' coterminal and encode a putative zinc finger transactivator protein. J Virol 66, 27632772.[Abstract]
Yamada, M., Sato, N., Taniyama, C., Ohtani, K., Arai, K. & Masai, H. (2002). A 63-base pair DNA segment containing an Sp1 site but not a canonical E2F site can confer growth-dependent and E2F-mediated transcriptional stimulation of the human ASK gene encoding the regulatory subunit for human Cdc7-related kinase. J Biol Chem 277, 2766827681.
Zerler, B., Moran, B., Maruyama, K., Moomaw, J., Grodzicker, T. & Ruley, H. E. (1986). Adenovirus E1A coding sequences that enable ras and pmt oncogenes to transform cultured primary cells. Mol Cell Biol 6, 887899.[Medline]
Zhang, Y. & Jones, C. (2001). The bovine herpesvirus 1 immediate-early protein (bICP0) associates with histone deacetylase 1 to activate transcription. J Virol 75, 95719578.
Received 21 October 2002;
accepted 10 December 2002.