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

The expression of the junB gene parallels the expression of the MHC class I genes in Adenovirus (Ad) transformed cells. In Ad12E1-transformed primary BRK cells both genes are transcriptionally repressed only when the 13S product of Ad12E1A is present. This indicates that repression of MHC class I and junB genes is a function of conserved region 3 (CR3) of the Ad12E1A protein. In Ad5-transformed BRK cells expression of these genes is unchanged. In established NRK cells, however, introduction of Ad12E1A does not cause repression of the MHC class I and junB genes, but in these cells Ad5E1A increases the expression of both MHC class I and junB. Using mutant Ad5E1A genes, it is shown that this activation is mediated by CR1. Introduction of a functional junB gene under the control of a heterologous promoter in Ad12E1-transformed BRK cells causes no increase in MHC class I expression. This demonstrates that the down-regulation of junB is not directly responsible for class I repression, but rather that both genes are coregulated by the Ad12E1 region.
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PMID:Co-regulated expression of junB and MHC class I genes in adenovirus-transformed cells. 190 58

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-(Ad)- E1A proteins carry two conserved domains (CR1 and CR2) required for transformation of primary rodent cells and essential for association with cellular proteins, including p105RB, p58cyclin A and p33cdk2. We show that in normal rat kidney 49F (NRK) cell lines expressing various mutant Ad5-E1A genes, CR2-, but not CR-1-, deletion mutants induce a typical transformed phenotype as characterized by morphology, absence of density arrest and loss of serum requirement. This indicates that induction of these transformed properties is a function of CR1. The fact that E1A proteins with deletions in CR2 show a greatly reduced association with RB, cyclin A and p33cdk2 suggests that these associations are dispensable for E1A-mediated transformation of NRK cells. Induction of the transformed properties is accompanied by a CR1-dependent increase in Proliferating Cell Nuclear Antigen and cyclin A gene expression. Elevated mRNA and protein levels of cyclin A were also found in Ad12-E1-transformed NRK cells but not in ras-transformed NRK cells. On the other hand, cyclin D expression is decreased in a CR1-dependent manner. Although Ad5-E1A proteins are sufficient to transform NRK cells, further deregulation of growth is obtained when Ad5-E1B proteins are co-expressed. One of the Ad5-E1B effects is the sequestration of the p53 protein into a cytoplasmic body containing the p53/Ad5-E1B-55 kD complex. Interestingly, in NRK cell lines expressing Ad5-E1B-55 kD, cyclin A could be detected not only in the nucleus but also in the cytoplasmic bodies. These results indicate that the deregulation of cell cycle control by the Adenovirus-E1 region may be due to a CR1-dependent alteration of the expression of cyclins A and D.
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PMID:Increased cyclin A and decreased cyclin D levels in adenovirus 5 E1A-transformed rodent cell lines. 851 Sep 23

The Adenovirus 5 E1A 12S gene is responsible for the establishment of immortalization of primary cells by Adenovirus. We have identified two mutants of 12S (30K and NTdl814), which, when coexpressed with wild-type 12S in primary baby rat kidney cells, were capable of suppressing the immortalizing function of the wild-type 12S gene, even when the mutant proteins were expressed at levels lower than wild type. 30K and NTdl814 did not affect the ability of the coexpressed 12S to activate the cell cycle, but have a suppressive effect on 12S-induced DNA synthesis and proliferation at late times in the immortalization pathway. Both the dominant negative mutants have a deletion in conserved region (CR)1 in the first exon of E1A, which encompasses one of the pRb-family binding regions. However, the mutants did not effect the binding of cellular proteins to full-length 12S. A suppressive effect on wild-type 12S was not observed with mutants that have lost any other region or function. In addition, expression of 30K, which is equivalent to the protein encoded by the 10S mRNA of E1A, inhibited E1A function in lytic cycle. Thus, loss of the CR1 seems to be a prerequisite for a mutant to have a dominant negative effect on E1A functions.
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PMID:Mutations in CR1 of E1A 12S yield dominant negative suppressors of immortalization and the lytic cycle. 920 Dec 16

The conserved region 3 (CR3) of the E7 protein of human papillomaviruses contains two CXXC motifs involved in zinc binding and in the homodimerization of the molecule. Studies have suggested that the intact CXXC motifs in the CR3 of HPV16 and HPV18 E7 are required for the in vitro transforming activity of these proteins. CR3 also contains a low affinity pRb binding site and is involved in the disruption of the E2F/Rb1 complex. E7 is structurally and functionally related to Adenovirus E1A protein, which also has two CXXC motifs in CR3. However, the Ad E1A transforming activity appears to be independent of the presence of such domains. In fact, this viral protein exists in vivo as two different forms of 289 and 243 amino acids. The shorter Ad E1A form (Ad E1A243), where both CXXC motifs are deleted by internal splicing, retains its in vitro transforming activity. We have investigated if the HPV16 E7 CR3 can be functionally replaced by the Ad E1A243 CR3, which lacks both CXXC motifs. A chimeric protein (E7/E1A243) containing the CR1 and CR2 of HPV16 E7 fused to the CR3 of Ad E1A 243 was constructed. The E7/E1A243 while not able to homodimerize in the S. cerevisiae two-hybrid system retains several of the properties of the parental proteins, HPV16 E7 and Ad E1A. It associates with the 'pocket' proteins, induces growth in soft agar of NIH3T3 cells and immortalizes rat embryo fibroblasts. These data suggest that the CXXC motifs in CR3 of E7 do not play a direct role in the transforming properties of this viral protein but probably are important for maintaining the correct protein configuration.
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PMID:The CXXC Zn binding motifs of the human papillomavirus type 16 E7 oncoprotein are not required for its in vitro transforming activity in rodent cells. 951 82

Adenovirus (Ad) E1A and human papillomavirus (HPV) E7 express homologous conserved regions (CRs) that mediate their shared biological functions. Despite their similarities, the expression of E1A sensitizes tumor cells to killing by NK cells and macrophages but the expression of E7 does not, a factor that may contribute to the dissimilar oncogenicities of Ad and HPV. This study was undertaken to define molecular differences between E1A and E7 that are responsible for the ability of E1A and the inability of E7 to sensitize cells to killing by NK cells and macrophages. Genetic mapping studies using human fibrosarcoma cells (H4) that stably expressed mutant forms of E1A showed that only those forms of E1A that interacted with the transcriptional coadaptor protein p300 sensitized cells to killing by NK cells and macrophages. E7 lacks the N-terminal p300-binding region present in E1A. Therefore, a chimeric E1A/E7 gene was constructed that included the N terminus and the CR1 (p300-binding) domain of E1A fused to CR2 and the C-terminal sequences of E7. The E1A/E7 protein interacted with p300 and pRb and immortalized primary mouse embryo fibroblasts (MEF). The expression of E1A/E7 sensitized H4 and MEF cells to killing by activated macrophages but not to killing by NK cells. Therefore, N-terminal differences between E1A and E7 that map to the E1A-p300 binding region accounted for differences in their abilities to sensitize cells to killing by macrophages. However, regions in addition to the E1A-p300 binding region are required to sensitize cells to killing by NK cells.
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PMID:Expression of an E1A/E7 chimeric protein sensitizes tumor cells to killing by activated macrophages but not NK cells. 1507 47

Neutrophils are effectors of the innate immune response to adenovirus vectors. Following the systemic administration of Cy2-labeled AdLuc in mice, flow cytometry and PCR analysis of liver leukocytes revealed that 25% of recruited neutrophils interacted with adenovirus vectors. In vitro, flow cytometry of human neutrophils incubated with Cy2-labeled AdLuc also demonstrated a significant interaction with adenovirus vectors. Fluorescence and electron microscopy confirmed vector internalization by neutrophils. The AdLuc-neutrophil interaction reduced vector transduction efficiency by more than 50% in coincubation assays in epithelium-derived cells. Adenovirus vector uptake by neutrophils occurred independently of coxsackievirus adenovirus receptor (CAR) and capsid RGD motifs, since neutrophils do not express CAR and uptake of the RGD-deleted vector AdL.PB* was similar to that of AdLuc. Furthermore, both AdLuc and AdL.PB* activated neutrophils and induced similar degrees of L-selectin shedding. Neutrophil uptake of AdLuc was dependent on the presence of complement and antibodies, since the interaction between AdLuc and neutrophils was significantly reduced when they were incubated in immunoglobulin G-depleted or heat-inactivated human serum. Blocking of complement receptor 1 (CD35) but not complement receptor 3 (CD11b/CD18) significantly reduced neutrophil uptake of AdLuc. Blocking of Fc gammaRI (CD64), Fc gammaRII (CD32), and Fc gammaRIII (CD16) individually or together also reduced neutrophil uptake of AdLuc, although less than blocking of CD35 alone. Combined CR1 and Fc receptor blockade synergistically inhibited neutrophil-AdLuc interactions close to baseline. These results demonstrate opsonin-dependent adenovirus vector interactions with neutrophils and their corresponding receptors.
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PMID:Neutrophils interact with adenovirus vectors via Fc receptors and complement receptor 1. 1628 62

Adenovirus continues to be an important model system for investigating basic aspects of cell biology. Interactions of several cellular proteins with E1A conserved regions (CR) 1 and 2, and inhibition of apoptosis by E1B proteins are required for oncogenic transformation. CR2 binds RB family members, de-repressing E2F transcription factors, thus activating genes required for cell cycling. E1B-19K is a BCL2 homolog that binds and inactivates proapoptotic BAK and BAX. E1B-55K binds p53, inhibiting its transcriptional activation function. In productively infected cells, E1B-55K and E4orf6 assemble a ubiquitin ligase with cellular proteins Elongins B and C, Cullin 5 and RBX1 that polyubiquitinates p53 and one or more subunits of the MRN complex involved in DNA double-strand break repair, directing them to proteosomal degradation. E1A CR3 activates viral transcription by interacting with the MED23 Mediator subunit, stimulating preinitiation complex assembly on early viral promoters and probably also the rate at which they initiate transcription. The viral E1B-55K/E4orf6 ubiquitin ligase is also required for efficient viral late protein synthesis in many cell types, but the mechanism is not understood. E1A CR1 binds several chromatin-modifying complexes, but how this contributes to stimulation of cellular DNA synthesis and transformation is not clear. E1A CR4 binds the CtBP corepressor, but the mechanism by which this modulates the frequency of transformation remains to be determined. Clearly, adenovirus has much left to teach us about fundamental cellular processes.
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PMID:Recent lessons in gene expression, cell cycle control, and cell biology from adenovirus. 1629 28

Human complement receptors 1 and 2 are well described as important regulators of innate and adaptive immune responses, having pivotal roles in regulating complement activation (CR1) and B-cell maturation/survival. In contrast, the role of the murine homologs of CR1 and CR2 (mCR1/2) have been primarily defined as modulating activation of the adaptive immune system, with very little evidence available about the role of mCR1/2 in regulating the innate immune responses to pathogens. In this paper, we confirm that mCR1/2 plays an important role in regulating both the innate and adaptive immune responses noted after Adenovirus (Ad)-mediated gene transfer. Our results uncovered a novel role of mCR1/2 in downregulating several complement-dependent innate immune responses. We also unveiled the mechanism underlying the complement-dependent induction of neutralizing antibodies to Ad capsids as a CR1/2-dependent phenomenon that correlates with B-cell activation. These results confirm that Ad interactions with the complement system are pivotal in understanding how to maximize the safety or potency of Ad-mediated gene transfer for both gene therapy and vaccine applications.
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PMID:CR1/2 is an important suppressor of Adenovirus-induced innate immune responses and is required for induction of neutralizing antibodies. 1955 32