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Query: UMLS:C0001486 (Adenovirus)
 3,125 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenovirus DNA polymerase (AdPol) contains three clusters of basic amino acids within the N-terminal 48 amino acids: RARR, which begins at amino acid 8, RRRVR, which begins at amino acid 25, and RARRRR, which begins at amino acid 41. These clusters are designated BS I, BS II, and BS III, respectively. (The amino acid codes are: R, arginine; A, alanine; V, valine.) Mutational analysis of these noncontiguous clusters showed that AdPol contains a novel organization of bipartite nuclear localization signals (NLS) that interact differentially to serve in the nuclear targeting of AdPol or of chimeric proteins in which AdPol is linked to Escherichia coli beta-galactosidase (beta-gal). The region containing BS I and BS II functioned interdependently as an NLS for the nuclear targeting of AdPol, for which BS III was dispensible. However, the region containing BS II and BS III constituted a second and more efficient bipartite NLS for the nuclear targeting of the AdPol-E. coli beta-gal fusion protein. Moreover, deletion or limited insertion of amino acids in the spacer region between BS II and BS III did not affect their nuclear targeting function for these fusion proteins. Chou-Fasman predictive analysis of protein secondary structure in the vicinity of the bipartite NLS sequences supports a model in which protein conformation in the spacer region may play an important role in bringing these clusters of basic amino acids into close proximity, allowing them to function as nuclear targeting signals for this class of nuclear proteins.
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PMID:Three basic regions in adenovirus DNA polymerase interact differentially depending on the protein context to function as bipartite nuclear localization signals. 177 81

Adenovirus VA RNAs (virus-associated RNAs) are small polymerase III transcripts that are required for efficient initiation of mRNA translation late in adenovirus infection. VAI RNA prevents double-stranded RNA (dsRNA) activation of the interferon-induced protein kinase (DAI kinase). Activation of this kinase results in phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2 alpha) and correlates with inhibition of translation initiation. In this report we show growth complementation of adenoviruses harboring deletions in the VAI gene in cell lines expressing a serine-to-alanine mutant of eIF-2 alpha. This serine-to-alanine mutant is resistant to phosphorylation by DAI kinase. These results directly show that the primary function of VAI RNA in the lytic adenovirus infection is the inhibition of eIF-2 alpha phosphorylation by DAI kinase and identify eIF-2 alpha as the target that mediates the effects of DAI kinase activation. Cells that express a mutant eIF-2 alpha will enable the isolation of specific host-range mutants for other types of viruses that are defective in the ability to inhibit DAI kinase.
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PMID:Complementation of adenovirus virus-associated RNA I gene deletion by expression of a mutant eukaryotic translation initiation factor. 259 57

Adenovirus early region 1A (E1A) encodes two acidic phosphoproteins which are required for transactivation of viral transcription, efficient viral DNA replication in phase G0-arrested human cells, and oncogenic transformation of rodent cells. Biochemical analysis of in vivo 32P-labeled adenovirus type 2 E1A proteins purified with monoclonal antibodies demonstrated that these proteins were phosphorylated at multiple serine residues. Two-dimensional phosphotryptic peptide maps of wild-type and mutant E1A proteins were used to locate a major site of E1A protein phosphorylation at serine-219 of the large E1A protein. Although this serine fell within a consensus sequence for phosphorylation by the cyclic AMP-dependent protein kinases, experiments with mutant CHO cells defective in these enzymes indicated that it was not. Oligonucleotide-directed mutagenesis was used to substitute an alanine for serine-219. This mutation prevented phosphorylation at this site. Nonetheless, the mutant was indistinguishable from the wild type for early gene transactivation, replication on G0-arrested WI-38 cells, and transformation of cloned rat embryo fibroblast cells.
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PMID:Genetic mapping of a major site of phosphorylation in adenovirus type 2 E1A proteins. 294 Mar 74

Adenovirus types 2, 4, 5, 6, 18, 21 and 27, were analyzed for N-terminal amino acids by use of (35)S-labeled phenylisothiocyanate of high specific radioactivity. Two free N-terminal amino acids, alanine and glycine, were found in these viruses in the molar ratio (alanine-glycine) of 2.5:1, with the exception of type 2 where the ratio was 3.6:1 and type 5 where the ratio was 5.5:1 Adenovirus type 2 was disrupted by acetone treatment, and two protein fractions were obtained after sucrose gradient centrifugation. One of these fractions, which was associated with the viral deoxyribonucleic acid and comprised approximately 18% of the total protein of the virus, was greatly enriched with respect to N-terminal alanine and glycine.
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PMID:Adenovirus proteins. II. N-terminal amino acid analysis. 562 73

Adenovirus 2 large plaque (Ip) mutants produce large clear plaques on human KB cells. These mutants are shown to be defective in inducing transformation of the established rat embryo cell line 3Y1. The Ip mutation was localized within one of the two transforming early gene blocks, E1b (map position 4.5 to 11.2) which codes for two major T antigens of 53 kd and 19 kd by marker transfer. The mutational defects in mutants Ip3 and Ip5 were analyzed by DNA sequence analysis and by analysis of viral E1 proteins. These results reveal that Ip3 and Ip5 mutations map within the 19 kd tumor antigen coding region. Mutant Ip3 has a single base pair change at the N terminus of 19 kd polypeptide, resulting in the substitution of valine for alanine. Mutant Ip5 has two mutational changes, one of which results in the substitution of tyrosine for aspartic acid near the N-terminal region. The second mutation changes the termination codon into a leucine codon, increasing the size of the 19 kd tumor antigen. These results provide direct genetic evidence for an essential role of the 19 kd tumor antigen in cell transformation and indicate that the N-terminal region of the 19 kd tumor antigen is an essential function domain for the induction of cell transformation.
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PMID:Adenovirus 2 Ip+ locus codes for a 19 kd tumor antigen that plays an essential role in cell transformation. 687 92

Adenovirus early region 1A (E1A) products induce DNA synthesis, transform primary rodent cells, and activate transcription factor E2F through complex formation with an array of cellular proteins via the E1A amino terminus and conserved regions 1 and 2 (CR1 and CR2). Interactions with the retinoblastoma tumor suppressor, pRb, and related proteins p107 and p130 rely somewhat on CR1 but largely on CR2, which contains a core binding sequence Leu-122-X-Cys-X-Glu. We introduced point mutations in CR2 to define such interactions more precisely. In human cells, alteration of any of the conserved residues within the binding core eliminated complex formation with pRb. Conversion of nonconserved Thr-123 to Pro (but not to either Ala or Ser) disrupted binding of pRb, presumably because of conformational changes in the binding core. No single E1A point mutant was completely defective in binding p107, suggesting that molecular interactions between E1A proteins and p107 clearly differ from those with pRb and p130. In general, the patterns of complex formation by E1A mutants in rat, monkey, and human cells were quite similar. All mutants which failed to bind significant amounts of pRb also failed to transform primary rat cells. Several mutants demonstrated selective binding to pRb, p107, and p130, but transforming activity corresponded largely with complex formation with pRb, regardless of the levels of interactions with p107 and p130. Mutants defective for binding of both pRb and p107 failed to induce the activity of transcription factor E2F; however, quite high levels were activated by E1A mutants that interacted with p107 alone. These results suggested that both pRb and p107 are important regulators of E2F activity but that complex formation with and activation of E2F by p107 are insufficient for cell transformation.
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PMID:Functional importance of complex formation between the retinoblastoma tumor suppressor family and adenovirus E1A proteins as determined by mutational analysis of E1A conserved region 2. 808 2

Adenovirus DNA polymerase (AdPol) exists as a complex with the preterminal protein (pTP) and is essential for both initiation and elongation stages of viral DNA replication. Recent evidence from our laboratory indicates that AdPol is a phosphoprotein and that the major in vivo phosphorylation site, serine 67, occurs within the consensus substrate recognition sequence for cdc2 kinases. In this study, we found that a protein kinase which also exhibits histone H1 phosphorylation activity is stably associated with AdPol. AdPol forms a multimeric complex with this histone H1 kinase and pTP in HeLa cells infected with adenovirus or coinfected with recombinant vaccinia viruses encoding AdPol and pTP. The associated protein kinase and the p34cdc2 kinase phosphorylate AdPol at the same sites which are utilized in vivo, suggesting that the p34cdc2 kinase or a related kinase may be involved in the in vivo phosphorylation of AdPol. Serine 67 is also one of the major in vitro phosphorylation sites, and the substitution of alanine for serine at this position abolishes DNA replication initiation activity of AdPol.
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PMID:Adenovirus DNA polymerase is phosphorylated by a stably associated histone H1 kinase. 834 26

Adenovirus E1B 19-kDa protein (19K) is a member of the Bcl-2 family of suppressors of apoptosis. The suppressors function through heterodimerization with the death promoters, Bax and related proteins, thus establishing a set point within the cell that determines whether or not apoptosis is executed in response to a death signal. Sequence similarities between 19K and Bcl-2 are largely restricted to short Bcl-2 homology (BH) domains that mediate interaction with Bax. The BH1 sequence in 19K is degenerate but nevertheless contains a conserved glycine residue found in all family members that when mutated to alanine in Bcl-2 results in loss of Bcl-2 function and ability to dimerize with Bax (Yin, X.-M., Oltvai, Z. N., and Korsmeyer, S. J. (1994) Nature 369, 321-323). Here, we show that the analogous mutation in BH1 of 19K also abrogates the anti-apoptotic properties of 19K and its ability to interact with Bax, thus establishing the critical importance of this residue within BH1 and the likely similarity of Bcl-2 and 19K function. In distinct contrast to Bcl-2, however, 19K interaction was not detected with Bad, a Bcl-2/Bcl-XL dimerizing protein that can potentially regulate a Bax middle dotBcl-2/Bcl-XL survival set point and reinstate susceptibility to a death signal. Furthermore, the anti-apoptotic function of 19K was not overcome by enforced expression of Bad in transfected cells. This feature of 19K may provide adenovirus with a selective advantage in evading premature induction of apoptosis by the host cell.
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PMID:Adenovirus E1B 19-kDa death suppressor protein interacts with Bax but not with Bad. 879 65

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the appearance of intracytoplasmic inclusions called Lewy bodies (LB) in dopamine neurons in the substantia nigra and the progressive loss of these neurons. Recently, mutations in the alpha-synuclein gene have been identified in early-onset familial PD, and alpha-synuclein has been shown to be a major component of LB in all patients. Yet, the pathophysiological function of alpha-synuclein remains unknown. In this report, we have investigated the toxic effects of adenovirus-mediated alpha-synuclein overexpression on dopamine neurons in rat primary mesencephalic cultures and in a rat dopaminergic cell line - the large T-antigen immortalized, mesencephalon-derived 1RB3AN27 (N27). Adenovirus-transduced cultures showed high-level expression of alpha-synuclein within the cells. Overexpression of human mutant alpha-synuclein (Ala(53)Thr) selectively induced apoptotic programmed cell death of primary dopamine neurons as well as N27 cells. The mutant protein also potentiated the neurotoxicity of 6-hydroxydopamine (6-OHDA). By contrast, overexpression of wild-type human alpha-synuclein was not directly neurotoxic but did increase cell death after 6-OHDA. Overexpression of wild-type rat alpha-synuclein had no effect on dopamine cell survival or 6-OHDA neurotoxicity. These results indicate that overexpression of human mutant alpha-synuclein directly leads to dopamine neuron death, and overexpression of either human mutant or human wild-type alpha-synuclein renders dopamine neurons more vulnerable to neurotoxic insults.
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PMID:Overexpression of human alpha-synuclein causes dopamine neuron death in rat primary culture and immortalized mesencephalon-derived cells. 1082 78

Adenovirus E1A mediates its effects on cellular transformation and transcription by interacting with critical cellular proteins involved in cell growth and differentiation. The amino terminus of E1A binds to CBP/p300 and associated histone acetyltransferases such as P/CAF. The carboxyl terminus binds to the carboxyl-terminal binding protein (CtBP), which associates with histone deacetylases. We show that 12S E1A can be acetylated by p300 and P/CAF and map one of the acetylation sites to Lys-239. This Lys residue is adjacent to the consensus CtBP binding motif, PXDLS. Mutation of Lys-239 to Gln or Ala blocks CtBP binding in vitro and disrupts the E1A-CtBP interaction in vivo. Peptide competition assays demonstrated that the interaction of E1A with CtBP is also blocked by Lys-239 acetylation. Supporting a functional role for Lys-239 in CtBP binding, mutation of this residue to Ala decreases the ability of E1A to block cAMP-regulated enhancer (CRE)-binding protein (CREB)-stimulated gene expression. Finally, we demonstrate that Lys-239 is acetylated in cells by using an antibody directed against an acetyl-Lys-239 E1A peptide. CtBP interacts with a wide variety of other transcriptional repressors through the PXDLS motif, and, in many instances, this motif is followed by a Lys residue. We suggest that acetylation of this residue by histone acetyltransferases, and the consequent disruption of repressor complexes, might be a general mechanism for gene activation.
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PMID:Acetylation of adenovirus E1A regulates binding of the transcriptional corepressor CtBP. 1111 58


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