The Rep68 Protein of Adeno-Associated Virus Type 2 Increases RNA Levels from the Human Cytomegalovirus Major Immediate Early Promoter

Wonderling, R S; Kyöstiö, S. R. M.; Walker, S.L.; Owens, Roland A.

doi:10.1006/viro.1997.8724

Cited by 15 publications

(12 citation statements)

References 65 publications

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“…As shown in Fig. 1C and D, the expression of both 16E1 and 16E2 in these experiments was driven by the CMV immediate-early promoter, which is only marginally affected by Rep (19,58,78). It may therefore be concluded that the effects of Rep were actually on DNA replication itself and not on the expression of the two HPV replicative proteins.…”

Section: Hpv16 Replication Is Inhibitedmentioning

confidence: 58%

Adeno-Associated Virus Type 2 Rep Protein Inhibits Human Papillomavirus Type 16 E2 Recruitment of the Transcriptional Coactivator p300

Marcello¹,

Massimi

Banks

et al. 2000

J Virol

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Infection by human adeno-associated virus type 2 (AAV2) is a possible protective factor in the development of cervical carcinomas associated with human papillomaviruses (HPV). The replicative proteins of AAV2 (Rep) have been implicated in the inhibition of papillomavirus replication and transforming activities, although the molecular events underlying these effects are poorly understood. We observed that each of the four forms of AAV2 Rep inhibited the E1-and E2-driven replication of oncogenic HPV type 16 (HPV16). Rep40, corresponding to the C-terminal domain of all Rep proteins, inhibited both HPV DNA replication and HPV16 E2-mediated transactivation. Rep40 specifically bound the N-terminal transactivation domain of HPV16 E2 both in vitro and in vivo. This interaction was found to specifically disrupt the binding of E2 to the cellular transcriptional coactivator p300. Accordingly, the inhibitory effect of Rep on HPV16 E2 transactivation was rescued by the overexpression of p300. These data indicate a novel role of Rep in the down-regulation of papillomaviruses through inhibition of complex formation between the HPV16 E2 transcriptional activator and its cellular coactivator, p300.

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Section: Hpv16 Replication Is Inhibitedmentioning

confidence: 58%

Adeno-Associated Virus Type 2 Rep Protein Inhibits Human Papillomavirus Type 16 E2 Recruitment of the Transcriptional Coactivator p300

Marcello¹,

Massimi

Banks

et al. 2000

J Virol

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“…Rep also has been shown to bind to the transcriptional activators PC4 (50), Sp1 (14,40), and Topors (49) and to the protein kinases PKA and PrKX (8,9). Recently, Cathomen et al (4) identified a cellular transcription factor, ZF5, that binds to the RBE and may contribute to the cellular repression of p19 seen here in the absence of Rep. Rep has also been shown to stimulate some promoters, for example, the c-sis and cytomegalovirus promoters (53,54). At least two mechanisms appear to be involved in Rep-mediated repression, as first suggested by Kyostio et al (24).…”

Section: Discussionmentioning

confidence: 86%

Studies of the Mechanism of Transactivation of the Adeno-Associated Virus p19 Promoter by Rep Protein

Lackner

Muzyczka

2002

J Virol

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During adeno-associated virus (AAV) type 2 productive infections, the p19 promoter of AAV is activated by the AAV Rep78 and Rep68 proteins. Rep-induced activation of p19 depends on the presence of one of several redundant Rep binding elements (RBEs) within the p5 promoter or within the terminal repeats (TR). In the absence of the TR, the p5 RBE and the p19 Sp1 site at position ؊50 are essential for p19 transactivation. To determine how a Rep complex bound at p5 induces transcription at p19, we made a series of p19 promoter chloramphenicol acetyltransferase constructs in which the p5 RBE was inserted at different locations upstream or downstream of the p19 mRNA start site. The RBE acted like a repressor element at most positions in the presence of both Rep and adenovirus (Ad), and the level of repression increased dramatically as the RBE was inserted closer to the p19 promoter. We concluded that the RBE by itself was not a conventional upstream activation signal and instead behaved like a repressor. To understand how the Rep-RBE complex within p5 activated p19, we considered the possibility that its role was to function as an architectural protein whose purpose was to bring other p5 transcriptional elements to the p19 promoter. In order to address this possibility, we replaced both the p5 RBE and the p19 Sp1 site with GAL4 binding sites. The modified GAL4-containing constructs were cotransfected with plasmids that expressed GAL4 fusion proteins capable of interacting through p53 and T-antigen (T-ag) protein domains. In the presence of Ad and the GAL4 fusion proteins, the p19 promoter exhibited strong transcriptional activation that was dependent on both the GAL4 fusion proteins and Ad infection. This suggested that the primary role of the p5 RBE and the p19 Sp1 sites was to act as a scaffold for bringing transcription complexes in the p5 promoter into close proximity with the p19 promoter. Since Rep and Sp1 themselves were not essential for transactivation, we tested mutants within the other p5 transcriptional elements in the context of GAL4-induced looping to determine which of the other p5 elements was necessary for p19 induction. Mutation of the p5 major late-transcription factor site reduced p19 activity but did not eliminate induction in the presence of the GAL4 fusion proteins. However, mutation of the p5 YY1 site at position ؊60 (YY1-60) eliminated GAL4-induced transactivation. This implicated the YY1-60 protein complexes in p19 induction by Rep. In addition, both basal p19 activity and activity in the presence of Ad increased when the YY1-60 site was mutated even in the absence of Rep or GAL4 fusion proteins. Therefore, there are likely to be alternative p5-p19 interactions that are Rep independent in which the YY1-60 complex inhibits p19 transcription. We concluded that transcriptional control of the p19 promoter was dependent on the formation of complexes between the p5 and p19 promoters and that activation of the p19 promoter depends largely on the ability of Rep and Sp1 to form a scaffold that positio...

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“…In the presence of helper virus, the two larger Rep proteins, Rep78 and Rep68, are required for AAV DNA replication (40,48,101), control of AAV transcription (9,58,60,61,66,77,111,129), alternative splicing of viral RNA (86), viral DNA packaging (24,31,54,83,119), and site-specific integration of viral DNA into human chromosome 19 (3,56). In addition, the expression of Rep proteins has been shown to inhibit Ad (21,22,51), simian virus 40 (SV40) (4,127), bovine papillomavirus (38), human immunodeficiency virus (1), and herpesvirus propagation (51,55); inhibit transcription from a variety of cellular and viral promoters (1,37,39,44,53,59,121,122); and efficiently arrest cells in the S phase (12,36,92,128). To accomplish these tasks, Rep is believed to interact with a variety of cellular and helper virus proteins, which have thus far been poorly defined.…”

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confidence: 99%

Identification of Cellular Proteins That Interact with the Adeno-Associated Virus Rep Protein

Nash

Chen

Salganik

et al. 2009

J Virol

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The Rep68 Protein of Adeno-Associated Virus Type 2 Increases RNA Levels from the Human Cytomegalovirus Major Immediate Early Promoter

Cited by 15 publications

References 65 publications

Adeno-Associated Virus Type 2 Rep Protein Inhibits Human Papillomavirus Type 16 E2 Recruitment of the Transcriptional Coactivator p300

Adeno-Associated Virus Type 2 Rep Protein Inhibits Human Papillomavirus Type 16 E2 Recruitment of the Transcriptional Coactivator p300

Studies of the Mechanism of Transactivation of the Adeno-Associated Virus p19 Promoter by Rep Protein

Identification of Cellular Proteins That Interact with the Adeno-Associated Virus Rep Protein

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