Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.48 (transcriptase)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mounting experimental evidence suggests that the TAT protein, released from human immunodeficiency virus-1 (HIV-1)-infected inflammatory cells, may genetically reprogram targeted cells within a localized environment to develop highly vascularized tumors of mesenchymal origin. The fibroblast growth factor (FGF) family of polypeptides has gained general acceptance as initiators of angiogenesis and functions as potent mitogens for mesoderm-derived cells. To evaluate a potential biological relationship between TAT and acidic FGF (FGF-1), primary murine embryonic fibroblasts either were transfected with the viral transactivator or were transduced (retrovirally mediated) with a secreted, chimeric form of the human polypeptide growth factor, human stomach tumor/Kaposi's sarcoma (hst/KS)FGF-1. Reverse transcriptase-polymerase chain reaction, Western blotting, in situ immunohistochemical, heparin affinity, DNA synthesis, and transient transfection techniques were used to confirm expression, localization, and functionality of the transgenes. Both transfected and transduced cells constitutively expressing either TAT or (hst/KS)FGF-1 adopted a transformed phenotype, maintained aggressive growth behavior, and demonstrated both induction of FGF-specific phosphotyrosyl proteins and nuclear association of FGF-1 and FGF-1 receptor. Increased levels of endogenous, murine FGF-1 mRNA (reverse transcriptase-polymerase chain reaction) and protein (immunoblot analysis) were apparent in both (hst/KS)FGF-1- and TAT-transformed cells. Medium conditioned by (hst/KS)FGF-1-transduced cells contained steady-state levels of biologically active FGF-1 which exhibited a representative molecular weight. Limited sodium dodecyl sulfate-polyacrylamide gel electrophoretic analysis of the conditioned medium from TAT-transformed cells demonstrated the appearance of FGF-1 as latent, high molecular weight complexes requiring reducing agents to activate full biological activity. Collectively, these results suggest that TAT induces the expression and secretion of FGF-1, which may be potentially relevant to the pathophysiological development of AIDS-Kaposi's sarcoma.
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PMID:The HIV-1 TAT protein induces the expression and extracellular appearance of acidic fibroblast growth factor. 754 39

Kaposi's sarcoma (KS) accounts for more than 15% of AIDS-related malignancies. The etiology of KS is unresolved but is postulated to be multifactorial, involving viruses and overexpression of cellular growth factors and/or oncogenes. Recently, herpesvirus-like sequences (KSHV) were identified with high prevalence in AIDS-KS (AKS), endemic KS, and in classic KS biopsies (CKS). To confirm the presence and the prevalence of the KSHV sequences, 18 CKS and 13 AKS samples were tested using polymerase chain reaction (PCR) analysis. To our knowledge this is the highest number of CKS samples that has ever been included in a single study, and it is also important that the biopsies were obtained from different institutions and geographical locations. KSHV sequences were detected in 100% of the AKS samples and 72% of the CKS biopsies using PCR analysis. The presence of the unique KSHV sequences was confirmed by direct sequencing of representative PCR products obtained from AKS and CKS samples. Reverse transcriptase (RT)-PCR experiments showed that the KSHV sequences were transcribed to mRNA in both AKS and CKS samples. Our results confirm that the putative new herpesvirus-like agent is associated with both AKS and CKS and may have an etiological role in the pathogenesis of this malignancy.
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PMID:Herpesvirus-like DNA sequences in classic Kaposi's sarcomas. 883 Jan 23

Primary effusion lymphoma (PEL) is a distinct clinicopathologic entity associated with Kaposi's sarcoma-associated herpes virus (KSHV). Several cytokines, including interleukin-6 (IL-6), basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF) may be important for survival of KS cells. However, little is known about the interaction of cytokines with KSHV-infected lymphocytes from PEL. Therefore, we investigated what cytokines were produced by KSHV-infected PEL cell lines (KS-1, BC-1, BC-2), what cytokine receptors were expressed by these cells, what response these cells had to selected cytokines, and what was the effect of IL-6 antisense phosphorothioated oligonucleotides. Reverse transcriptase-polymerase chain reaction (RT-PCR) and protein studies showed that these three cell lines produced IL-10, IL-6, and the receptors for IL-6. The granulocyte macrophage colony-stimulating factor (GM-CSF), IL-1beta, IL-8, IL-12, bFGF, PDGF, and c-kit transcripts were not detected in the cell lines. High levels (0.7 to 5 ng/mL/10(6) cells/48 hours) of IL-6 protein were consistently detected in supernatants of the cell lines by enzyme-linked immunosorbent assay (ELISA) tests. In clonogenic assays, interferon-alpha (IFN-alpha) and IFN-gamma suppressed the clonal growth of the PEL cells, but GM-CSF, IL-4, IL-6, IL-8, IL-10, and oncostatin M did not change it. We examined for several autocrine loops that have been suggested to occur in KS. Experiments using antisense oligonucleotides showed that the clonal growth of KS-1 and BC-1 was nearly 100% inhibited by IL-6 antisense oligonucleotides (10 micromol/L), but not at all by either oligonucleotides (</=10 micromol/L) to IL-6 sense, IL-6 scrambled, viral IL-6 (vIL-6) antisense, or IL-10 antisense. Furthermore, the IL-6 antisense oligonucleotides had no effect on two B-cell lymphoma cell lines, which were not infected with KSHV. Addition of IL-6 antibody did not inhibit clonal growth of any of the cell lines. Taken together, we have defined the cytokines and their receptors expressed on PEL cells and have found that these cells synthesized IL-6 and IL-6 receptors; interruption of this pathway by IL-6 antisense oligonucleotides specifically prevented the growth of these cells. These findings will offer potential new therapeutic strategies for PEL.
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PMID:Mechanisms of growth control of Kaposi's sarcoma-associated herpes virus-associated primary effusion lymphoma cells. 951 48

Primary effusion lymphomas (PELs), which are rare lymphomas associated with Kaposi's sarcoma-associated herpesvirus (or human herpesvirus-8) infection, present as malignant lymphomatous effusions in body cavities. Because PELs prefer liquid growth, we hypothesized that increased vascular permeability would be required for effusions to form. We found that the PEL cell lines BC-1, BCP-1, and BCBL-1 produce high levels of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF). Reverse transcriptase-polymerase chain reaction analysis of RNA from the PEL cell lines amplified the 3 VEGF-secreted isoforms: VEGF/VPF(121), VEGF/VPF(145), and VEGF/VPF(165). Two of the PEL cell lines expressed the VEGF/VPF receptor Flt-1, but VEGF/VPF did not stimulate proliferation in these cells. Most (13/14) control SCID/beige mice inoculated intraperitoneally with BCBL-1 cells and subsequently observed or treated with control antibodies developed effusion lymphoma of human cell origin with prominent bloody ascites. In contrast, none (0/9) of the mice treated with a neutralizing antihuman VEGF/VPF antibody developed ascites and effusion lymphoma. These results demonstrate that VEGF/VPF is critical to BCBL-1 growth as effusion lymphoma in mice and suggest that VEGF/VPF stimulation of vascular permeability may be critical to the pathogenesis of PELs.
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PMID:Role of vascular endothelial growth factor/vascular permeability factor in the pathogenesis of Kaposi's sarcoma-associated herpesvirus-infected primary effusion lymphomas. 1059 69

Human herpesvirus 8 (HHV-8) has been causally linked to Kaposi's sarcoma (KS). There is significant homology between some HHV-8 genes and cellular genes including D-type cyclin (vCYC), G protein coupled receptor (vGCR), macrophage inflammatory proteins (vMIP-I, vMIP-II), bcl-2 (vBCL2), interferon regulatory factor-1 (vIRF1), interleukin-6 (vIL6), and complement-binding protein (vCBP). In this study, we analyzed expression of these viral homologs and HIV-1 Tat by reverse-transcriptase polymerase chain reaction (RT-PCR) coupled with Southern blot hybridization in AIDS-KS (AKS) tissue, classic KS tissue(CKS), and peripheral blood mononuclear cells, and phorbol ester (TPA)-treated and untreated HHV-8 positive lymphoma cells (BCBL1). While vCYC (AKS 6 of 6; CKS 3 of 3), vMIP-I (AKS 5 of 6, CKS 3 of 3), vBCL2 (AKS 6 of 6; CKS 3 of 3), and vIRF1 (AKS 5 of 6, CKS 3 of 3) transcripts were detected in both AKS and CKS, vGCR and HIV-1 Tat were expressed only in AKS samples (vGCR: AKS 3 of 6, CKS 0 of 3; Tat: AKS 4 of 6, CKS 0 of 3). vMIPII, vCBP, and vIL6 expression were not detected in any KS samples. Since vGCR expression is limited to AKS, it is possible that vGCR is activated by HIV-1 Tat. These results suggest that HIV-1 Tat may contribute to AKS pathogenesis through the tumorigenic and angiogenic effects of vGCR.
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PMID:Differential expression of the HHV-8 vGCR cellular homolog gene in AIDS-associated and classic Kaposi's sarcoma: potential role of HIV-1 Tat. 1066 20

The presence of human herpesvirus-8 DNA sequences, as well as an overexpression of human interleukin-6 and human cyclin D1 in myofibroblastic cells of inflammatory myofibroblastic tumor (inflammatory pseudotumor), has recently been reported. We describe the pattern of human herpesvirus-8 gene expression in five cases of pulmonary inflammatory myofibroblastic tumor. Reverse transcriptase-polymerase chain reaction (RT-PCR), with several positive and negative controls, was performed to detect mRNA of 11 open reading frames encoded by human herpesvirus-8 in lytic and latent stages of viral replicative cycle. We found molecular transcripts from ORF16, ORFK13, and ORF72 in the five cases and from ORFK2 in four of five neoplasms. The corresponding encoded proteins were human homologous oncoproteins (viral cyclin-D), inflammatory cytokines (viral IL-6), and inhibitors of apoptotic pathways (viral FLIP and viral Bcl-2), mostly expressed in a latent viral replicative stage. The rest of open reading frames examined included mainly lytic-associated genes and showed no expression. The spectrum of expressed viral genes is not the same as can be observed in Kaposi's sarcoma or multicentric Castleman's disease, suggesting that human herpesvirus-8 plays a different role in the pathogenesis of its associated diseases. These differences may be related to either cell-specific or immunologic host factors.
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PMID:Human herpesvirus-8 genes are expressed in pulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor). 1217 Jan 1

Primary effusion lymphoma is a form of diffuse large B-cell lymphoma with neoplastic cells largely limited to proliferation within major body cavities. Human herpes virus-8 is both integral to and required for an unequivocal diagnosis of primary effusion lymphoma. Prior methods for virus identification include DNA extraction with Southern blot analysis or in situ hybridization from paraffin-embedded samples. Our aim is to examine the utility of human herpesvirus-8 identification performed directly on smears from effusion samples by reverse transcriptase in situ polymerase chain reaction in patients with primary effusion lymphoma. Smears and cell block of body cavity fluids from five patients with effusions (three pleural, one peritoneal, and one both pleural and peritoneal) were examined microscopically by conventional Papanicolaou and Romanowsky (Diff-Quik) staining, and by reverse transcriptase in situ polymerase chain reaction for human herpesvirus-8 detection. In situ hybridization was performed also for Epstein-Barr virus (EBER-1, -2), T-cell receptor-beta, and kappa (kappa) and lambda (lambda) mRNA in all cases. Five adults ranged from 40-81 years of age. Three adults were HIV positive, one was a renal transplant recipient, and the oldest patient (Case 3) had the unusual distinction of a normal immune status. Two of three HIV-seropositive patients had concurrent Kaposi sarcoma. All samples were cytologically similar with lymphocytes having large-cell, plasmablastic, and immunoblastic morphology. Malignant cells from effusions were as follows: human herpesvirus-8 positive (all five cases), exhibited kappa monoclonal light chain (five cases), Epstein-Barr virus positive (three cases), and T-cell beta-gene receptor positive (two cases). Diffuse large B-cell lymphoma was evident in one peritoneal nodule (< 10% human herpesvirus-8 positive cells in contrast to > 90% positive in effusions, all kappa positive). Six other tissue specimens (lung, bone marrow, spleen, lymph node) were human herpesvirus-8 negative, and showed no evidence of lymphoma. Reverse transcriptase in situ polymerase chain reaction demonstrated near-complete restriction of human herpesvirus-8-infected malignant lymphoid cells to those in body cavities. Definitive diagnosis of primary effusion lymphoma is possible directly from cytologic smears/cell block by combining cytologic morphology with reverse transcriptase in situ polymerase chain reaction detection of human herpesvirus-8.
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PMID:Primary effusion lymphoma: cytopathologic diagnosis using in situ molecular genetic analysis for human herpesvirus 8. 1221 12

CD9, a member of the transmembrane 4 superfamily, is involved in cell adhesion, migration, and tumor metastasis. Little is known about its vascular expression pattern. In this study, we investigated CD9 expression on endothelial cells in the mucosa of the head and neck and compared it with vascular tumors. Using immunohistochemistry, expression of CD9 was studied in 17 samples of head and neck mucosa and skin (laryngeal mucosa: n = 2, oral: n = 6, and epidermis: n = 9) and a variety of vascular tumors (lymphangiomas: n = 9, juvenile nasopharyngeal angiofibromas: n = 4, hemangiomas: n = 7, angiosarcomas: n = 5, and Kaposi's sarcomas: n = 7) and compared with the expression of CD34 and PAL-E (blood vessel markers) and the lymphatic marker podoplanin. Regular lymphatic endothelium and lymphangiomas were strongly positive for CD9 and podoplanin but were mostly negative for PAL-E and CD34. By contrast, blood vessel endothelium and hemangiomas were strongly positive for PAL-E and CD34 but were mostly negative for CD9 and podoplanin. Weak to moderate CD9 reactivity was also observed on EC of juvenile nasopharyngeal angiofibromas, angiosarcomas, and Kaposi's sarcomas. Expression of CD9 by lymphatic EC was confirmed by reverse-transcriptase PCR and Western blot analyses. CD9 may be useful as a marker for lymphatic EC. It could promote the adherence of inflammatory and tumor cells to lymphatic EC and participate in the growth and maintenance of the lymphatic capillary net.
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PMID:CD9 expression on lymphatic vessels in head and neck mucosa. 1455 86

Factor XIIIa-positive dendrocytes are abundant within the dermis and have been implicated in the pathogenesis of various disorders, including AIDS-related Kaposi's sarcoma. Purified cultures of factor XIIIa-positive normal dermal dendrocytes have not as yet been achieved. 12E2 is a cloned cell line derived from superficial murine dermis where factor XIIIa-positive dendrocytes are abundant. Subconfluent cultures of 12E2 demonstrate polydendritic cell contours with thin, elongated membranous projections. These cells express Factor XIIIa and VCAM-1 by immunohistochemistry and by Western blot analysis of 12E2 cell lysates. 12E2 cells also constitutively express the Langerhans-cell-related epitope DEC-205, detected by NLDC-145 antibody and the CD80 co-stimulatory molecule, as well as Ia antigen on exposure to interferon-gamma. Cells so treated exhibit significant ability to present alloantigens in vitro. 12E2 cells are shown to express mRNA for numerous cytokines, including interleukin (IL)-1alpha, IL-1beta, IL-5, IL-6, IL-7, tumor necrosis factor-alpha and granulocyte macrophage-colony stimulating factor, by reverse-transcriptase polymerase chain reaction followed by Southern blot hybridization. Microinjection of 12E2 cells, but not 3T3control fibroblasts, into footpads of syngeneic and SCID mice results in lesions that mimic the histology and immunohistochemistry of human Kaposi's sarcoma. In aggregate, these data indicate that 12E2 cells 1) share lineage characteristics with factor XIIIa-positive dermal dendrocytes, 2) produce mRNA for numerous cytokines and are cytokine responsive to interferon-gamma, and 3) behave in vivo in a manner that resembles Kaposi's sarcoma, a condition known to involve proliferation of human dermal dendrocytes.
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PMID:12E2: a cloned murine dermal cell with features of dermal dendrocytes and capacity to produce pathologic changes resembling early Kaposi's sarcoma. 1457 82

In 1983 Luc Montagnier and his colleagues claimed to have discovered a novel retrovirus presently known as human immunodeficiency virus (HIV). By 1984 HIV was almost universally accepted to be the cause of AIDS. However, 20 years later, HIV cannot account for the phenomena for which the retroviral hypothesis was proposed, namely, Kaposi's sarcoma, decrease in T4 lymphocytes and thus the opportunistic infections in AIDS patients which were assumed to be the direct results of this decrease. Agents other than HIV to which patients belonging to the AIDS risk groups are exposed cause decrease in T4 cells. Neither have the main predictions of the HIV hypothesis been fulfilled. HIV seropositivity in the developed countries still remains restricted to the original high risk groups, no HIV vaccine exists, and no successful animal model has been developed. In this communication, we critically analyse the evidence which in 1983 was claimed to prove the existence of HIV. The phenomena which Montagnier and his colleagues considered proof for the existence of HIV are detection of reverse transcriptase activity; the presence of retrovirus-like particles in the culture; immunological reactivity between proteins from the culture supernatant which, in sucrose density gradients, banded at the density of 1.16 g/ml ("purified virus") and antibodies in a patient's (BRU) serum. Reverse transcriptase activity can be found in viruses other than retroviruses and in all normal cells. Reverse transcription can be brought about not only by the enzyme reverse transcriptase but also by normal, cellular DNA polymerases. Retrovirus-like particles are ubiquitous in cultures not infected with retroviruses, especially in conditions employed by Montagnier et al. From the reaction between proteins in the "purified virus" and antibodies in the patient serum Montagnier concluded that the proteins were HIV proteins and the antibodies were HIV antibodies. Since all antibodies are polyspecific, from such a reaction it is not possible to define the origin of even one reactant let alone both. Even if this were possible, since Montagnier's "purified virus" did not contain particles with the "morphology typical of retroviruses", the proteins cannot be retroviral. We conclude that, these phenomena are non-specific to retroviruses and thus cannot be considered proof for the existence of a unique retrovirus HIV.
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PMID:A critique of the Montagnier evidence for the HIV/AIDS hypothesis. 1532 2


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