Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001486 (Adenovirus)
3,125 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 12 S and 13 S E1A cDNAs from both the Adenovirus (Ad) nononcogenic type 5 and the oncogenic type 12 were overexpressed in an insect cell/baculovirus system. Upon infection of Spodoptera frugiperda cells, the production of E1A proteins reached a level of about 15 micrograms/10(6) cells. The E1A proteins are highly soluble and apparently are processed authentically. They are readily recognized by various antibodies and display phosphorylation patterns similar to those of E1A proteins synthesized in mammalian cells. Single-step immunoaffinity chromatography was used to purify the Ad5 E1A proteins to near homogeneity under nondenaturing conditions. The Ad5 and Ad12 E1A proteins are able to form complexes with the retinoblastoma susceptibility gene product (Rb) and other cellular proteins. Interestingly, the presence of a cellular extract seems to be a prerequisite for association between highly purified E1A and Rb polypeptides.
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PMID:Expression, purification, and functional characterization of adenovirus 5 and 12 E1A proteins produced in insect cells. 138 52

Adenovirus E1A transforming function requires two distinct regions of the protein. Transforming activity is closely linked with the presence of a region designated conserved domain 2 and the ability of this region to bind the product of the cellular retinoblastoma tumor suppressor gene. We have investigated the biological properties of the second transforming region of E1A, which is located near the N terminus. Transformation-defective mutants containing deletions in the N terminus (deletion of residues between amino acids 2 and 36) were deficient in the ability to induce DNA synthesis and repress insulin enhancer-stimulated activity. The function of the N-terminal region correlated closely with binding of the 300-kilodalton E1A-associated protein and not with binding of the retinoblastoma protein. These results indicate that transformation by E1A is mediated by two functionally independent regions of the protein which interact with different specific cellular proteins and suggest that the 300-kilodalton E1A-associated protein plays a major role in E1A-mediated cell growth control mechanisms.
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PMID: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. 214 44

Adenovirus type 12 has high oncogenic potential in newborn rodents. Moreover, adenovirus 12 induces retinoblastoma-like tumours in baboons and transforms in vitro human embryo retinoblasts. Since adenovirus-transformed cells contain adenovirus transforming gene sequences, the detection of adenovirus 12 transforming gene in tumour cell DNA can provide evidence for or against a possible aetiological role of adenovirus 12 in retinoblastoma. In this experiment, cell DNAs from six retinoblastomas were assayed for adenovirus 12 transforming gene sequences by spot hybridization and Southern blot hybridization, using the labelled EcoRI-C fragment of adenovirus 12 DNA as a probe (the far left 16.5% of the viral genome). No adenovirus 12 transforming gene sequences were detected at the level of 0.1 or 0.5 copy of the probe per diploid cell DNA in all of six retinoblastomas.
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PMID:Analysis of retinoblastoma for human adenovirus type 12 genome. 688 78

Adenovirus infection leads to E1A-dependent activation of the transcription factor E2F. E2F has recently been identified in complexes with cellular proteins such as the retinoblastoma protein (pRB) and the two pRB family members p107 and p130. E1A dissociates E2F from these cellular proteins, and another viral protein, E4 (ORF6/7), can bind to E2F. The binding of E4 to E2F induces the formation of a stable DNA-binding complex containing the two proteins, and stimulation of the adenovirus E2 early promoter can occur. Recent studies have shown that E2F is the combined activity of several proteins, and we demonstrate here that heterodimerization of two of these proteins, E2F-1 and DP-1, is required for stable binding to E4. This complex is formed independently of DNA binding and requires the C-terminal 20 amino acids of E4. Furthermore, the binding is dependent on a region of E2F-1 between amino acids 284 and 358. This region of E2F-1 is conserved in E2F-2 and E2F-3, and deletion of this region drastically reduces the transcriptional activity of the molecule without affecting DP-1 binding, suggesting that this region of the E2F transcription factors is involved in regulating their activity. Our experiments also demonstrate that pRB binding to the E2F-1/DP-1 heterodimer prevents the formation of an E2F-1/DP-1/E4 complex.
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PMID:Heterodimerization of the transcription factors E2F-1 and DP-1 is required for binding to the adenovirus E4 (ORF6/7) protein. 803 3

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 E1A proteins inhibit expression of the collagenase gene but activate expression of the c-jun gene. Both effects are mediated by TPA-responsive elements (TREs), the binding sites for members of the AP-1 transcription factor family. By a process that is independent of the retinoblastoma gene product, E1A distinguishes between different AP-1 factors: in vivo binding of Jun/Jun homodimers and Jun/Fos heterodimers to the collagenase TRE is totally blocked by E1A while, in contrast, there is no inhibition of Jun/ATF-2 binding to the TRE sequences in the c-jun promoter. Altered phosphorylation of the DNA binding domain of cJun is not involved in the inhibition of cJun/cJun and cJun/cFos binding. E1A does, however, cause hyperphosphorylation of the transactivation domain of cJun, which is likely to be responsible for the enhanced c-jun transcription by E1A mediated through cJun/ATF-2 heterodimers.
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PMID:Adenovirus E1A negatively and positively modulates transcription of AP-1 dependent genes by dimer-specific regulation of the DNA binding and transactivation activities of Jun. 825 81

Adenovirus early region 1A (E1A) oncogene-encoded sequences essential for transformation- and cell growth-regulating activities are localized at the N terminus and in regions of highly conserved amino acid sequence designated conserved regions 1 and 2. These regions interact to form the binding sites for two classes of cellular proteins: those, such as the retinoblastoma gene product, whose association with the E1A products is specifically dependent on region 2, and another class which so far is known to include only a large cellular DNA-binding protein, p300, whose association with the E1A products is specifically dependent on the N-terminal region. Association between the E1A products and either class of cellular proteins can be disrupted by mutations in conserved region 1. While region 2 has been studied intensively, very little is known so far concerning the nature of the essential residues in the N-terminal region, or about the manner in which conserved region 1 participates in the binding of two distinct sets of cellular proteins. A combination of site-directed point mutagenesis and monoclonal antibody competition experiments reported here suggests that p300 binding is dependent on specific, conserved residues in the N terminus, including positively charged residues at positions 2 and 3 of the E1A proteins, and that p300 and pRB bind to distinct, nonoverlapping subregions within conserved region 1. The availability of precise point mutations disrupting p300 binding supports previous data linking p300 with cell cycle control and enhancer function.
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PMID:Identification of specific adenovirus E1A N-terminal residues critical to the binding of cellular proteins and to the control of cell growth. 841 79

Adenovirus E1A encodes two nuclear phosphoproteins that can transform primary rodent fibroblasts in culture. Transformation by E1A is mediated at least in part through binding to several cellular proteins, including the three members of the retinoblastoma family of growth inhibitory proteins. We report here the cloning of a novel murine cDNA whose encoded protein interacts with both adenovirus type 5 and type 12 E1A proteins. The novel E1A-interacting protein shares significant sequence homology with ubiquitin-conjugating enzymes, a family of related proteins that is involved in the proteasome-mediated proteolysis of short-lived proteins. Highest homology was seen with a Saccharomyces cerevisiae protein named UBC9. Importantly, the murine E1A-interacting protein complements a cell cycle defect of a S. cerevisiae mutant which harbors a temperature-sensitive mutation in UBC9. We therefore named this novel E1A-interacting protein mUBC9. We mapped the region of E1A that is required for mUBC9 binding and found that the transformation-relevant conserved region 2 of E1A is required for interaction.
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PMID:mUBC9, a novel adenovirus E1A-interacting protein that complements a yeast cell cycle defect. 882 23

Group C adenovirus is latent in human tissues and can malignantly transform cells. The purpose of this study was to investigate the association between this virus and lung cancer. We investigated latent adenoviral infection using the nested polymerase chain reaction and in situ hybridization in transbronchial biopsy specimens from patients with small-cell lung cancer and non-small-cell lung cancer. The polymerase chain reaction was performed on DNA extracts with two sets of primers directed at a 261-base-pair target sequence of the E1A region of the adenoviral genome. In situ hybridization was performed on histological sections using DNA representing the entire adenovirus type 5 genome. E1A target DNA was present in 11 (31%) of 35 cases of small-cell lung cancer but in none of the 40 cases of non-small-cell lung cancer (P < 0.01). Of the 11 cases found positive by PCR, 8 were positive for adenovirus DNA by in situ hybridization. Adenovirus was prominent in tumor cells in 5 of the 8 cases, and in normal epithelial cells in the 3 remaining cases. Adenovirus DNA was not detected by in situ hybridization in specimens in which E1A DNA was not detected by the polymerase chain reaction. Small-cell lung cancer has mutations or deletions in the p53 and retinoblastoma genes more frequently than are found in non-small-cell lung cancer. Therefore, we speculate that adenovirus infection might participate in the pathogenesis of SCLC by producing mutation in these genes, rather than by inhibiting the function of these proteins.
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PMID:Detection of group C adenovirus DNA in small-cell lung cancer with the nested polymerase chain reaction. 926 May 89

Adenovirus type 12 (Ad12) infection of human cells induces four chromosomal fragile sites corresponding to the U1 small nuclear RNA (snRNA) genes (the RNU1 locus), the U2 snRNA genes (RNU2), the U1 snRNA pseudogenes (PSU1), and the 5S rRNA genes (RN5S). Ad12-induced fragility of the RNU2 locus requires U2 snRNA transcriptional regulatory elements and viral early functions but not viral replication or integration, or chromosomal sequences flanking the RNU2 locus. We now show that Ad12 cannot induce the RNU1, RNU2, or PSU1 fragile sites in Saos-2 cells lacking the p53 and retinoblastoma (Rb) proteins but that viral induction of fragility is rescued in these cells when the expression of wild-type p53 or selected hot-spot mutants (i.e., V143A, R175H, R248W, and R273H) is restored by transient expression or stable retroviral transduction. We also observed weak constitutive fragility of the RNU1 and RNU2 loci in cells belonging to xeroderma pigmentosum complementation groups B and D (XPB and XPD) which are partially defective in the ERCC2 (XPD) and ERCC3 (XPB) helicase activities shared between the repairosome and the RNA polymerase H basal transcription factor TFIIH. We propose a model for Ad12-induced chromosome fragility in which interaction of p53 with the Ad12 E1B 55-kDa transforming protein (and possibly E4orf6) induces a p53 gain of function which ultimately perturbs the RNA polymerase II basal transcription apparatus. The p53 gain of function could interfere with chromatin condensation either by blocking mitotic shutdown of U1 and U2 snRNA transcription or by phenocopying global or local DNA damage. Specific fragilization of the RNU1, RNU2, and PSU1 loci could reflect the unusually high local concentration of strong transcription units or the specialized nature of the U1 and U2 snRNA transcription apparatus.
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PMID:Adenovirus type 12-induced fragility of the human RNU2 locus requires p53 function. 955 7


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