The human cytomegalovirus 86K immediate early (IE) 2 protein requires the basic region of the TATA-box binding protein (TBP) for binding, and interacts with TBP and transcription factor TFIIB via regions of IE2 required for transcriptional regulation

Caswell, Richard; Hagemeier, Christian; Chiou, Chuang-Jiun; Hayward, Gary S.; Kouzarides, Tony; Sinclair, John

doi:10.1099/0022-1317-74-12-2691

Cited by 132 publications

(149 citation statements)

References 30 publications

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“…The magnitude of the IL1B promoter response to IE2 probably relates to its ability to interact with multiple components of the transcriptional machinery including TBP and Spi-1, among others, at amino acids 291-364 Caswell et al, 1993;Fortunato et al, 1997;Jupp et al, 1993;Kim et al, 2000;Lukac et al, 1997;Lukac et al, 1994;Pizzorno et al, 1991;Scully et al, 1995). Here the list of interacting partners is expanded with the addition of C/EBPβ.…”

Section: Discussionmentioning

confidence: 99%

“…This report demonstrated that the deleted sequence is necessary, but did not determine whether it is sufficient for interaction with Spi-1. This same region was shown by others to contain one of two nuclear localization sequences (NLS), one of three TBP binding regions, and is required for IE2 interaction with at least seven other transcription factors (Fig 1c) Caswell et al, 1993;Fortunato et al, 1997;Jupp et al, 1993;Kim et al, 2000;Lukac et al, 1997;Lukac et al, 1994;Pizzorno et al, 1991;Scully et al, 1995). Recently, we reported the existence of a mutually exclusive three-way interaction involving associations between any two of the proteins: IE2 ; C/EBPβ; and Spi-1 (Fig 1d) (Listman et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of IL-1β transcription by peptides derived from the hCMV IE2 transactivator

Listman¹,

Race²,

Walker-Kopp³

et al. 2008

Molecular Immunology

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The immediate early (IE) proteins of human cytomegalovirus (hCMV) have diverse roles in directing viral and host cell transcription. Among these is the ability of IE2 to induce transcription of the IL1B gene that codes for IL-1β in monocytes. This function is partially explained by interaction between IE2 and the host cell transcription factor Spi-1/PU.1 (Spi-1). We now show that maximal IE2 function also depends on productive interactions localizing to two C/EBP sites on the IL1B promoter suggesting either bi-or tri-molecular interactions between IE2, Spi-1 and C/EBPβ at two different locations on the promoter. The IE2 interaction region on Spi-1 was previously mapped to the DNAbinding ETS domain and overlaps the region of Spi-1 that interacts with the transcription factor C/ EBPβ, a factor known to be critical for the induction of IL1B in response to Toll/IL-1 receptor (TIR) family signal transduction. The Spi-1 interacting region of IE2 maps to amino acids 315-328, a sequence that also interacts with the bZIP domain of C/EBPβ. An expression vector coding for amino acids 291-364 of IE2 can suppress LPS induction of a cotransfected IL1B enhancer-promoter fragment in a monocyte cell line. This inhibition is likely the result of competition between Spi-1 and C/EBPβ, thus blunting gene induction.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of IL-1β transcription by peptides derived from the hCMV IE2 transactivator

Listman¹,

Race²,

Walker-Kopp³

et al. 2008

Molecular Immunology

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“…Therefore, IE2p86 seems to act as a transcription factor that exerts a broad activation pattern. Since IE2p86 interacts with the basal transcription factors TBP (Hagemeier et al, 1992a;Sommer et al, 1994) and TFIIB (Caswell et al, 1993) and with distinct cellular transcription factors such as CREB, Ap-1, Egr-1, Spi-1/PU.1 or Sp1, protein interactions are believed to be essential for transactivation (Lukac et al, 1994;Lang et al, 1995;Scully et al, 1995;Yoo et al, 1996;Yurochko et al, 1997;Wara-Aswapati et al, 1999).In this report we provide evidence for the mechanism by which HCMV upregulates ICAM-1 on the cell surface of endothelial cells as well as fibroblasts. We show that the regulatory proteins IE2p86 and pp71 act as strong synergistic inducers of the ICAM-1 promoter.…”

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confidence: 99%

Synergistic induction of intercellular adhesion molecule-1 by the human cytomegalovirus transactivators IE2p86 and pp71 is mediated via an Sp1-binding site

Kronschnabl¹,

Stamminger²

2003

Journal of General Virology

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Human cytomegalovirus (HCMV) infection of transplant recipients is frequently associated with allograft vasculopathy and rejection. One potential mechanism is vascular injury from HCMVtriggered, immunologically mediated processes. HCMV infection has been shown to increase the expression of intercellular adhesion molecule-1 (ICAM-1). The objective of this study was to determine the molecular basis of HCMV-enhanced ICAM-1 gene expression. Transient transfection experiments identified the IE2p86 protein as a potent activator of the ICAM-1 promoter. The tegument protein pp71 showed a strong synergistic effect on IE2p86-mediated ICAM-1 promoter activation. Mutagenesis experiments defined a DNA element from 2110 to 242 relative to the transcription start site as responsive for IE2p86. Further point mutations within this DNA element identified an Sp1-binding site that was essential for strong synergistic activation by IE2p86 and pp71. To confirm the activation of ICAM-1 gene expression, human fibroblasts (HFF) as well as endothelial cells (HUVEC) were infected with recombinant IE2p86-and pp71-expressing baculoviruses, respectively. In FACS analysis, a synergistic induction of ICAM-1 was detectable when cells were co-infected with the two recombinant baculoviruses. These findings clearly demonstrate that IE2p86 and pp71 are crucial regulatory factors for HCMV-induced ICAM-1 upregulation. INTRODUCTIONHuman cytomegalovirus (HCMV), a b-herpesvirus, is a ubiquitous human pathogen with a prevalence of infection in the adult population of 50-90 %. Although HCMV rarely causes severe disease on primary infection in immunocompetent people, it represents a highly pathogenic agent for immunosuppressed patients such as transplant recipients, as well as newborns, and establishes lifelong persistence in the infected host (Alford & Britt, 1990). So far, the exact site of latency is still uncertain; monocytes, haematopoietic precursor cells and endothelial cells have been discussed as potential reservoirs for latent HCMV (Fish et al., 1995;Sindre et al., 1996).Recent evidence suggests that HCMV not only causes acute infection in transplanted patients but may also be associated with extensive transplant vasculopathy, ultimately leading to chronic allograft rejection (Grattan et al., 1989;Skowronski et al., 1993;Koskinen et al., 1993;Lautenschlager et al., 1997a;Schnitzler et al., 1997;Borchers et al., 1999). One of the molecular mechanisms underlying the acceleration of vascular disease processes by HCMV infection may be enhancement of transplant immunogenicity. Several studies indicate that this involves the HCMV-induced upregulation of cellular adhesion molecules, which augments the adherance and infiltration of inflammatory cells that are capable of promoting vascular disease (Einsele et al., 1994;Lemstrom et al., 1995;Steinhoff et al., 1995;Koskinen et al., 1996;Yilmaz et al., 1996; Martelius et al., 1998;Waldman et al., 1998;Lautenschlager et al., 1999;The et al., 2001). For instance, cell culture experiments have demonstrated that...

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“…Cyclin E and cdks are highly activated after HCMV infection of HFF cells (4,(18)(19)(20). In addition, GST-IE86 fusion protein interacts in vitro with a variety of transcription factors that include histone acetyltransferase, CREB, TBP, TEF-1, TFIIB, and TAFII-130, and cell cycle regulatory factors that include p53, RB, and p21 (11,14,16,(21)(22)(23)(24)(25)(26)(27). The Rb protein has also been reported to bind the IE86 protein in vivo (22,28).…”

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confidence: 99%

“…12 and 13). The IE86 protein encoded by the IE2 gene (UL122) is a strong transactivator that interacts with factors of the basal-transcription machinery (14)(15)(16)(17). The IE86 protein activates cyclin E gene expression (18), which is essential for progression of the cell cycle into the S phase.…”

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confidence: 99%

Effect of the human cytomegalovirus IE86 protein on expression of E2F-responsive genes: A DNA microarray analysis

Song

Stinski

2002

Proc. Natl. Acad. Sci. U.S.A.

108

100

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The human cytomegalovirus 86K immediate early (IE) 2 protein requires the basic region of the TATA-box binding protein (TBP) for binding, and interacts with TBP and transcription factor TFIIB via regions of IE2 required for transcriptional regulation

Cited by 132 publications

References 30 publications

Inhibition of IL-1β transcription by peptides derived from the hCMV IE2 transactivator

Inhibition of IL-1β transcription by peptides derived from the hCMV IE2 transactivator

Synergistic induction of intercellular adhesion molecule-1 by the human cytomegalovirus transactivators IE2p86 and pp71 is mediated via an Sp1-binding site

Effect of the human cytomegalovirus IE86 protein on expression of E2F-responsive genes: A DNA microarray analysis

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