Growth arrest of Epstein–Barr virus immortalized B lymphocytes by adenovirus-delivered ribozymes

Huang, Shuang; Stupack, Dwayne G.; Mathias, Patricia; Wang, Yibing; Nemerow, Glen R.

doi:10.1073/pnas.94.15.8156

Cited by 39 publications

(39 citation statements)

References 33 publications

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“…Then, replication-deficient adenovirus type 5 encoding green fluorescent protein (GFP) was added to the cell suspension at a multiplicity of infection (m.o.i.) of 50 or 500 (45). After 1 h at 37°C, virus not internalized was digested by incubation of the cells with 0.03% trypsin and 0.35 mM EDTA for 5 min at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Mechanisms and Consequences of Affinity Modulation of Integrin αVβ3 Detected with a Novel Patch-engineered Monovalent Ligand

Pampori¹,

Hato²,

Stupack³

et al. 1999

Journal of Biological Chemistry

156

153

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Integrin ␣ V ␤ 3 mediates diverse responses in vascular cells, ranging from cell adhesion, migration, and proliferation to uptake of adenoviruses. However, the extent to which ␣ V ␤ 3 is regulated by changes in receptor conformation (affinity), receptor diffusion/clustering (avidity), or post-receptor events is unknown. Affinity regulation of the related integrin, ␣ IIb ␤ 3 , has been established using a monovalent ligand-mimetic antibody, PAC1 Fab. To determine the role of affinity modulation of ␣ V ␤ 3 , a novel monovalent ligand-mimetic antibody (WOW-1) was created by replacing the heavy chain hypervariable region 3 of PAC1 Fab with a single ␣ V integrin-binding domain from multivalent adenovirus penton base. Both WOW-1 Fab and penton base bound selectively to activated ␣ V ␤ 3 , but not to ␣ IIb ␤ 3 , in receptor and cell binding assays. ␣ V ␤ 3 affinity varied with the cell type. Unstimulated B-lymphoblastoid cells bound WOW-1 Fab poorly (apparent K d ‫؍‬ 2.4 M), but acute stimulation with phorbol 12-myristate 13-acetate increased receptor affinity >30-fold (K d ‫؍‬ 80 nM), with no change in receptor number. In contrast, ␣ V ␤ 3 in melanoma cells was constitutively active, but ligand binding could be suppressed by overexpression of ␤ 3 cytoplasmic tails. Up-regulation of ␣ V ␤ 3 affinity had functional consequences in that it increased cell adhesion and spreading and promoted adenovirus-mediated gene transfer. These studies establish that ␣ V ␤ 3 is subject to rapid regulated changes in affinity that influence the biological functions of this integrin.Integrins mediate cell adhesion and signaling during many developmental, physiological, and pathological processes (1-4). The ␤ 3 integrin family includes ␣ IIb ␤ 3 , often referred to as the fibrinogen receptor, and ␣ V ␤ 3 , the vitronectin receptor. ␣ IIb ␤ 3 is confined to megakaryocytes and platelets and is required for platelet aggregation through interactions with Arg-Gly-Asp (RGD)-containing adhesive ligands, including fibrinogen and von Willebrand factor (5). ␣ V ␤ 3 is more widely expressed in proliferating endothelial cells, arterial smooth muscle cells, osteoclasts, platelets, and certain subpopulations of leukocytes and tumor cells (6, 7). The list of cognate ligands for ␣ V ␤ 3 overlaps that for ␣ IIb ␤ 3 , but includes others, such as osteopontin, matrix metalloproteinase-2, and adenovirus penton base, which do not interact with ␣ IIb ␤ 3 (6, 8 -10). In the adult organism, ␣ V ␤ 3 has been implicated in processes ranging from wound healing to tumor angiogenesis (11), arterial restenosis (12), osteoporosis (13), tumor progression (14), and adenovirus internalization (8).One fundamental function of integrins is ligand binding, which in many cases is rapidly regulated by a process variously referred to as "integrin activation," "inside-out signaling," or "affinity/avidity modulation" (15-19). Integrin activation encompasses at least two events: 1) modulation of receptor affinity through conformational changes in the ␣␤ heterodimer and 2) modulation...

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Section: Methodsmentioning

confidence: 99%

Mechanisms and Consequences of Affinity Modulation of Integrin αVβ3 Detected with a Novel Patch-engineered Monovalent Ligand

Pampori¹,

Hato²,

Stupack³

et al. 1999

Journal of Biological Chemistry

156

153

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“…Moreover, EBNA1 has little effect on transcription of an EBNA1-dependent reporter integrated at most sites in cell DNA (20,29). Alternatively, EBNA1 might alter cell growth or survival through an interaction with a cell protein (30)(31)(32)(33)(34)(35)(36)(37)(38)(39). However, once EBV DNA has integrated into cell DNA, EBNA1 is not required for LCL growth, and LCLs with EBNA1-null mutant EBV genomes are indistinguishable from wild-type EBV-transformed B lymphocytes in their growth (12).…”

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confidence: 99%

Epstein-Barr virus nuclear antigen 1 does not induce lymphoma in transgenic FVB mice

Kang

Yasui

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The lymphoma-inducing potential of Ig heavy-chain enhancer-and promoter-regulated Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) was evaluated in three transgenic FVB mouse lineages. EBNA1 was expressed at a higher level in transgenic B220(؉) splenocytes than in EBV-infected lymphoblastoid cell lines. EBNA1 was also expressed in B220(؊) transgenic splenocytes and thymocytes. Before killing and assessments at 18 -26 months, EBNA1-transgenic mice did not differ from control mice in mortality. At 18 -26 months EBNA1-transgenic mice did not differ from littermate control in ultimate body weight, in spleen size or weight, in lymph node, kidney, liver, or spleen histology, in splenocyte fractions positive for cluster of differentiation (CD)3 , CD4, CD8, CD62L, B220, CD5, IgM, IgD, MHC class II, CD11b, or CD25, or in serum IgM, IgG, or total Ig levels. Lymphomas were not found in spleens or other organs of 18-to 26-month-old EBNA1-transgenic (n ‫؍‬ 86) or control (n ‫؍‬ 45) FVB mice. EBNA1-transgenic lineages had a higher pulmonary adenoma prevalence than did littermate controls (39% versus 7%). However, the adenoma prevalence was not higher in EBNA1-transgenic mice than has been described for FVB mice, and EBNA1 was not expressed in normal pulmonary epithelia or adenomas.cancer ͉ herpesvirus ͉ latent ͉ persistence I n initial lymphocyte infection, Epstein-Barr Virus (EBV) causes B lymphocyte proliferation through a latency III program of expression of six nuclear proteins (EBNAs), two different integral membrane proteins, two small RNAs, and Bam A-initiated transcripts (1, 2). Although, in vitro, latency III-infected lymphocytes are able to grow endlessly as lymphoblastoid cell lines (LCLs), EBV proteins expressed in latency III-infected cells, in vivo, engender T cell responses that limit infected cell survival. EBV mostly persists long term in nonproliferating, latency I-or II-infected B cells that express EBNA1 or EBNA1 and latent infection membrane proteins, respectively (2-4). Latency I or latency II are also characteristic of Burkitt's lymphoma, Hodgkin's disease, and nasopharyngeal carcinoma (2). EBNA1 is expressed in almost all latent EBV infections and associated malignant diseases.EBNA1 enables efficient EBV episome replication, transcription, and maintenance in latently infected dividing cells (5-21). EBNA1 amino acids 379-641 include a dimerization and DNAbinding domain, which binds cognate 30-bp inverted repeat DNA sequences. EBV origin of plasmid replication (oriP) consists of 20 tandem cognate 30-bp repeats and four others 1 kbp away in a dyad symmetry (22). OriP has intrinsic origin activity. EBNA1 enhances oriP-dependent episome replication, transcription, and maintenance (7,8). EBNA1 amino acids 1-378 are necessary for chromosome association, transcriptional enhancement, and episome persistence, although not for initial DNA replication (21,(23)(24)(25). Within amino acids 1-378 is an irregular glycine͞alanine repeat, which inhibits EBNA1 processing through the proteasome͞TAP pathway (26,27).Becau...

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“…This initially suggested to us that the RGD sequence was important for mediating viral transduction of murine B cells as has been shown for human B cells. 3,7,14 However, inhibition studies (shown in Figure 9) did not reveal a major role for RGD-integrin interactions in the transduction of LPS-activated B cells. Other possibilities include (1) the fiber knob of the Adz.PB(FLAG) may cause steric hindrance of the anti-FLAG antibody from interacting effectively with both the FLAG epitope and the Fc receptor 17 or (2) the sequence of the penton base near the RGD motifs is important for interactions with unknown cell surface proteins.…”

Section: Discussionmentioning

confidence: 99%

“…[3][4][5][6][7] Adenovirus infects a host cell by interaction of at least two coat proteins with two cell surface receptors. The fiber protein interacts with the coxsackievirus-adenovirus receptor 3 (CAR).…”

Section: Introductionmentioning

confidence: 99%

Efficient transduction of murine B lymphocytes and B lymphoma lines by modified adenoviral vectors: enhancement via targeting to FcR and heparan-containing proteins

Wickham

Keegan

2001

Gene Ther

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Murine lymphocytes are relatively refractory to efficient transfection or retroviral gene transduction. Adenovirus has been used as a vector to transduce a wide variety of cell types. Several advantages of adenoviruses are their ability to transduce non-cycling cells and to transduce the majority of cells in a population. Unfortunately, lymphocytes are not susceptible to infection with conventional adenovirus. Therefore, to express genes efficiently in murine B cells, we tested the ability of genetically modified adenovirus to transduce the ␤-galactosidase gene. We found that adenovirus containing polylysine in the fiber knob was able to efficiently transduce lipopolysaccharide (LPS)-activated splenic B cells and the B lymphoma line M12.4.1; greater than 80% of the cells expressed ␤-galactosidase activity. However, small resting B cells did not express activity unless treated with LPS after infection. This transduction was mediated by inter-

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Growth arrest of Epstein–Barr virus immortalized B lymphocytes by adenovirus-delivered ribozymes

Cited by 39 publications

References 33 publications

Mechanisms and Consequences of Affinity Modulation of Integrin αVβ3 Detected with a Novel Patch-engineered Monovalent Ligand

Mechanisms and Consequences of Affinity Modulation of Integrin αVβ3 Detected with a Novel Patch-engineered Monovalent Ligand

Epstein-Barr virus nuclear antigen 1 does not induce lymphoma in transgenic FVB mice

Efficient transduction of murine B lymphocytes and B lymphoma lines by modified adenoviral vectors: enhancement via targeting to FcR and heparan-containing proteins

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