The Structure and Function of the Adenovirus Major Late Promoter

Young, C. S. H.

doi:10.1007/978-3-662-05597-7_8

Cited by 36 publications

(43 citation statements)

References 123 publications

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“…Prior to DNA replication, the MLP is active at low levels, with transcription proceeding only as far as the L3 region and mRNA production restricted to the L1-52/55K and i leader proteins (5). The specific activation of the MLP requires binding of Ad-infected cell-specific transcription factor complexes to the downstream element (DE) of the MLP (6). The Ad L4-22K protein is thought to be the minimal factor required for MLP activation, but additional components, such as IVa2, are required to obtain the maximum activation observed at late times of infection (7).…”

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confidence: 99%

The Adenovirus L4-22K Protein Has Distinct Functions in the Posttranscriptional Regulation of Gene Expression and Encapsidation of the Viral Genome

Guimet

Hearing

2013

J Virol

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The adenovirus L4-22K protein is multifunctional and critical for different aspects of viral infection. Packaging of the viral genome into an empty capsid absolutely requires the L4-22K protein to bind to packaging sequences in cooperation with other viral proteins. Additionally, the L4-22K protein is important for the temporal switch from the early to late phase of infection by regulating both early and late gene expression. To better understand the molecular mechanisms of these key functions of the L4-22K protein, we focused our studies on the role of conserved pairs of cysteine and histidine residues in the C-terminal region of L4-22K. We found that mutation of the cysteine residues affected the production of infectious progeny virus but did not interfere with the ability of the L4-22K protein to regulate viral gene expression. These results demonstrate that these two functions of L4-22K may be uncoupled. Mutation of the histidine residues resulted in a mutant with a similar phenotype as a virus deficient in the L4-22K protein, where both viral genome packaging and viral gene expression patterns were disrupted. Interestingly, both mutant L4-22K proteins bound to adenovirus packaging sequences, indicating that the paired cysteine and histidine residues do not function as a zinc finger DNA binding motif. Our results reveal that the L4-22K protein controls viral gene expression at the posttranscriptional level and regulates the accumulation of the L4-33K protein, another critical viral regulator, at the level of alternative pre-mRNA splicing.H uman adenoviruses (Ad) consist of a nonenveloped icosahedral capsid with a linear double-stranded viral genome of ϳ36,000 bp. Many questions remain about the basic biology of Ad infection. In particular, virus assembly for complex eukaryotic viruses is relatively poorly understood. Understanding the molecular mechanisms of the viral life cycle is critical for development of strategies for treatment of Ad infections and for the use of Ad as a gene therapy vector. The Ad5 genome contains five early transcription units (E1A, E1B, E2, E3, and E4), which encode ϳ25 proteins that are expressed before viral DNA replication, and a set of delayed mRNAs, which encode proteins IX and IVa2, synthesized at the onset of DNA replication. These early and intermediate transcripts encode proteins with various roles during infection, including transcriptional regulation, viral DNA replication, inhibition of cellular antiviral responses, and inhibition of immune responses (1-4). Following DNA replication, a single major late transcription unit (MLTU) is transcribed and includes five different groups of mRNAs (L1 to L5) that encode capsid structural proteins and proteins that promote virus assembly, direct Ad genome packaging, and serve regulatory functions (2). The Ad major late promoter (MLP) drives transcription from the MLTU regions L1 to L5, producing all late mRNAs by alternative splicing and polyadenylation of a primary transcript. Prior to DNA replication, the MLP is active at low leve...

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The Adenovirus L4-22K Protein Has Distinct Functions in the Posttranscriptional Regulation of Gene Expression and Encapsidation of the Viral Genome

Guimet

Hearing

2013

J Virol

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“…The IVa2 protein interacts with the L1 52/55-kDa protein (14), another viral gene product involved in the packaging process (13,15). Interestingly, the core sequences of the packaging domain are also found in the DE elements (34), transcriptional elements located downstream of the Ad major late promoter (MLP) (33). The IVa2 protein was shown to bind these sequences and transactivate the MLP (20,32).…”

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The L4 22-Kilodalton Protein Plays a Role in Packaging of the Adenovirus Genome

Ostapchuk

Anderson

Chandrasekhar

et al. 2006

J Virol

131

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“…Because both E3 genes or fiber genes are only expressed during replication cycle after infection of adenovirus (29,30), it would be expected that the transgene can be only expressed in tumor cells if oncolytic adenovirus is applied. To fully evaluate therapeutic potential of oncolytic adenoviral vector carrying this novel expression system, we have constructed novel doublecontrolled oncolytic adenovirus, in which 6.7K/gp19K of E3 genes was replaced with potent antitumor gene mda-7/IL-24.…”

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confidence: 99%

Treatment of Cancer with a Novel Dual-Targeted Conditionally Replicative Adenovirus Armed with mda-7/IL-24 Gene

Luo

Xia

Zhang

et al. 2008

Clinical Cancer Research

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Purpose: Recent studies showed that oncolytic adenoviruses not only have capacity for destruction of tumors but also can be used as potential vectors to express therapeutic genes for therapy of cancer. However, better specificity and mode of transgene expression are required to improve the efficacy and safety if this vector is applied for clinical application. Experimental Design: In this study, we have created adenoviral replication-based transgene expression system by replacement of 6.7K/gp19K of E3 genes with EGFP and IL-24 genes so that expression of transgenes should be controlled by adenoviral E3 promoter. Transgene expression, viral replication capacity, and cytotoxicity have been studied in tumor and normal cells. Antitumor efficacy was evaluated in animal model with established tumor. Results: Our data showed that expression of IL-24 could be detected at 6 h and reached the maximal level at 48 h after infection in tumor cells. The expression level was 14 times higher than that induced by cytomegalovirus promoter. Low level of IL-24 could be detected in normal cells only until 72 h after infection.The substitution of 6.7K/gp19K of E3 genes with transgenes did not affect viral replication in tumor cells. Strong cytotoxicity was observed only in tumor cells after infection with AdCN205-IL-24. Treatment of the established tumors induced high level of local expression of IL-24 in tumor cells and resulted in tumor regression. Conclusions: Our data showed that AdCN205-IL-24 can provide potent and safe vector for the therapy of cancer.

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The Structure and Function of the Adenovirus Major Late Promoter

Cited by 36 publications

References 123 publications

The Adenovirus L4-22K Protein Has Distinct Functions in the Posttranscriptional Regulation of Gene Expression and Encapsidation of the Viral Genome

The Adenovirus L4-22K Protein Has Distinct Functions in the Posttranscriptional Regulation of Gene Expression and Encapsidation of the Viral Genome

The L4 22-Kilodalton Protein Plays a Role in Packaging of the Adenovirus Genome

Treatment of Cancer with a Novel Dual-Targeted Conditionally Replicative Adenovirus Armed with mda-7/IL-24 Gene

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