Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Very late antigen-4 (VLA-4) composed of alpha 4 and beta 1, a member of the beta 1-integrin subfamily, facilitates cell-to-cell interaction with vascular cell-adhesion molecule-1 (VCAM-1) on endothelial cells (EC). Attachment of blood-borne tumor cells to EC is a crucial step for hematogenous metastasis, and VLA-4-positive tumor cells can attach to EC by binding to VCAM-1. Renal-cell cancer (RCC) reveals proportionally greater percentages of metastases than other carcinomas at initial diagnosis. We investigated whether VLA-4 is expressed on RCC, and how such expression on RCC correlates with the metastatic potential of RCC. Immunohistochemical staining on 66 primary and 4 metastatic RCC showed that 4 out of 4 metastatic and 5 out of 8 primary RCC from patients with lung and/or brain metastases expressed alpha 4 and beta 1 chains. On the other hand, 13 of 58 RCC without metastases expressed alpha 4 chain, alpha 4 and beta 1 expressions were also detected on 5 out of 5 human RCC cell lines, ACHN, KRC/Y, A498, Caki1 and Caki2, by flow-cytometric analysis. Reverse-transcriptase-polymerase-chain-reaction (RT-PCR), followed by Southern-blot hybridization with cDNA probe for a alpha 4 chain, also confirmed mRNA production in 4 out of 5 RCC cell lines. Furthermore, adhesion of alpha 4-positive RCC cell lines to human umbilical-vein endothelial cells (HUVEC) was augmented by treatment of HUVEC with tumor necrosis factor-alpha (TNF-alpha). This adhesion was inhibited by anti-alpha 4 or anti-VCAM-1 antibodies, suggesting that VLA-4-VCAM-1 interaction was involved in the adhesion between RCC cells and HUVEC. Taken together, VLA-4 on RCC cells might play a crucial role in their hematogenous metastasis.
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PMID:Possible significance of VLA-4 (alpha 4 beta 1) for hematogenous metastasis of renal-cell cancer. 789 40

The first step in the homing of hematopoietic progenitor cells (HPCs) from the peripheral blood to the bone marrow involves an adhesion molecule-dependent contact with human bone marrow endothelial cells (HBMECs). In the present study we describe the constitutive expression of two of these molecules, E-selectin and vascular cell adhesion molecule-1 (VCAM-1), on endothelial cells of hematopoietic tissues. Immunophenotypic analysis of tissue sections of hematopoietically active (human adult and fetal bone marrow, fetal spleen, fetal liver, and adult spleen with extramedullary hematopoiesis) and inactive tissues (human adult spleen, lymph node, appendix, and liver; and fetal lung and fetal intestine) revealed that E-selectin and VCAM-1 are selectively expressed on endothelial cells of adult and fetal hematopoietic organs. These results were validated by means of reverse-transcriptase polymerase chain reaction. Adhesion studies revealed that binding of normal mobilized peripheral blood HPCs to HBMECs was completely inhibited by preincubation of HBMECs with anti-E-selectin (ENA2), whereas no effect of anti-VCAM-1 (1G11B1) was detected. These results suggest that E-selectin plays a role in the homing of HPCs and that its constitutive expression on endothelial cells of hematopoietic organs may be essential in the initial step of the homing process.
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PMID:Constitutive expression of E-selectin and vascular cell adhesion molecule-1 on endothelial cells of hematopoietic tissues. 854 3

The adhesion molecule intercellular adhesion molecule-1 (ICAM-1), in addition to its membrane-associated form (mICAM-1), also exists as a soluble form (sICAM-1). sICAM-1 is capable of binding to lymphocyte function associated antigen-1 (LFA-1) molecules, and production of sICAM-1 is therefore thought to have immunomodulatory consequences. The present study, which employed normal human keratinocytes as a model for sICAM-1-producing cells, was conducted to determine the mechanism responsible for the production of sICAM-1 and to develop a strategy for specific inhibition of sICAM-1 production. Stimulation of keratinocytes with recombinant human gamma-interferon (rhIFN-gamma) induced both expression of mICAM-1 and production of sICAM-1. Western blot analysis revealed that keratinocyte-derived sICAM-1, compared to mICAM-1, had a smaller molecular size, approximately a 7-kD difference. Neither by Northern blot analysis nor by reverse-transcriptase polymerase chain reaction (RT-PCR) was any evidence for alternatively spliced ICAM-1 mRNA obtained. Addition of the protease inhibitors iodoacetamide and E-64, however, inhibited the production of sICAM-1 in a dose-dependent manner. The involvement of proteolytic cleavage in the production of sICAM-1 was corroborated in minimal peptide protection assays, in which minimal peptides covering the potential cleavage site of ICAM-1 were added to sICAM-1-producing keratinocytes. One of these peptides, ICAM cleavage inhibitory peptide (ICAM-CIP), inhibited the production of sICAM-1 without affecting mICAM-1 expression. These studies demonstrate that sICAM-1 production in human keratinocytes is due to proteolytic cleavage, and that the oligopeptide ICAM-CIP may specifically inhibit this mechanism. The capacity of ICAM-CIP to selectively prevent production of sICAM-1 may be useful for the development of novel therapeutic approaches relevant for the management of inflammation and cancer.
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PMID:Analysis of the production of soluble ICAM-1 molecules by human cells. 864 65

The herpes simplex virus thymidine kinase gene (HSV-TK) in combination with ganciclovir (GCV), is currently being used in gene therapy-based clinical trials for cancer treatment. Its therapeutic effect is based on a "bystander effect" whereby HSV-TK gene-modified tumor cells are toxic to nearby unmodified tumor cells when exposed to the antiviral drug GCV. We have recently hypothesized that the in vivo mechanism of this bystander effect is due to alterations in the tumor microenvironment in response to release of cytokines and an infiltration of leukocytes after treatment with HSV-TK gene-modified tumor cells and GCV, which results in tumor regression. Expression of B7, a recently identified costimulatory molecule that is important for T-cell stimulation, has been shown to be modulated by stimulatory cytokines interferon-gamma, tumor necrosis factor-alpha, and inhibited by interleukin-10. In the present study, we investigated whether the cytokines released after HSV-TK and GCV treatment could include the expression of the costimulatory molecules B7-1 and B7-2 and the adhesion molecule (ICAM)-1 in the tumor. Furthermore, we investigated whether this altered environment affected the antitumor properties of host lymphocytes. An in vitro model was developed to establish the effects of HSV-TK gene-modified tumor cells and GCV on tumor infiltrating cells. The murine macrophage cell line (IC21) was exposed to either supernatants or cell lysates collected from a mixture of HSV-TK-transduced (KBALB-STK) and non-transduced (KBALB) murine fibrosarcoma tumor cells previously exposed to GCV (experimental). Immunohistochemical analysis showed a significant expression (P < .0001) of B7-1 and B7-2 post exposure of IC21 cells to either supernatant or lysate. In contrast, the level of expression in IC21 cells exposed to the control lysate or supernatant remained unchanged for B7-1 and B7-2. In vivo analysis for B7-1 and B7-2 expression by immunohistochemistry in tumor tissues from experimental mice receiving HSV-TK gene-modified tumor cells and GCV treatment showed a significant expression of B7.1 (35%, P < .0001) and B7.2 (38.2%, P < .0001) on tumor-infiltrating mononuclear cells. In contrast, tumor-bearing control animals showed low levels of B7-2 expression (5.8%), whereas B7-1 was undetectable, as confirmed by reverse-transcriptase polymerase chain reaction. In addition, a significant up-regulation of ICAM expression (50%) on tumor tissues was observed in the experimental group (P = .0317) as compared with the control group (25%). Furthermore, T cells isolated from experimental mice showed a significant in vitro proliferative response (p = .0202) when exposed to syngeneic tumor cells as compared with the control group. These data demonstrated that the use of HSV-TK gene-modified tumor cells and GCV as a suicide gene in the treatment of an intraperitoneal tumor resulted in the expression of the B7 costimulatory molecules and ICAM-1 adhesion molecule and enhanced proliferative response of host T cells. These findings help to understand the mechanism of tumor cell killing in vivo using HSV-TK gene-modified tumor cells.
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PMID:Expression of costimulatory molecules: B7 and ICAM up-regulation after treatment with a suicide gene. 898 40

Cytokine responses in human host-protective immunity to malaria have yet to be completely elucidated. No data appear to exist on the cytokine patterns in non-human primate models immunized with malarial antigens. Expression of mRNA transcripts of 10 cytokines, the adhesion molecule ICAM-1 and inducible nitric oxide synthase (iNOS) in peripheral-blood mononuclear cells (PBMC) from nine Aotus monkeys was analysed by reverse-transcriptase PCR. Five of the monkeys had been immunized with multiple-antigen peptides (MAP) of the Plasmodium vivax circumsporozoite protein and two with constructs of the P. falciparum merozoite surface protein-1 (MSP-1). The other two monkeys served as non-immunized controls. PBMC were cultured for 24 h after stimulation with phytohaemagglutinin mitogen, MAP and MSP-1 antigens. Elevated expression of interleukin-6 (IL-6), IL-10, IL-12, tumour necrosis factor-alpha (TNF-alpha), TNF-beta and iNOS was seen in response to the MAP. Monkeys immunized with either P. falciparum MSP r190L or synthetic 190L peptides expressed predominantly the type-1 cytokines (IL-1 beta, IL-12, interferon-gamma, TNF-alpha, TNF-beta) characteristic of splenic, cell-mediated activity with macrophage activation and nitric oxide production.
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PMID:Expression of cytokine genes in Aotus monkeys immunized with synthetic and recombinant Plasmodium vivax and P. falciparum antigens. 979 28

ICAM-1 is an Ig-like cell adhesion molecule expressed by several cell types, including the endothelium. Cross-linking of ICAM-1 on the surface of different cell types has previously been shown to cause an increase in cellular activation within the cytoplasm. In this study, we have compared signaling events following ligation of ICAM-1 by cross-linking with mAbs with events after activation of HUVEC by TNF. ICAM-1 cross-linking caused activation of Erk-1 and the AP-1 transcription factor complex, without any increase in NF-kappaB activity, in contrast to TNF stimulation. Transcription of VCAM-1 mRNA was observed by reverse-transcriptase PCR after ICAM-1 cross-linking, with no associated transcription of E-selectin. This was reflected by the presence of VCAM-1 protein after immunoprecipitation, without E-selectin expression, in ICAM-1 cross-linked cells. In contrast, mRNA and protein for both VCAM-1 and E-selectin were observed in TNF-treated HUVEC, as expected. Addition of the MEK (MAP/Erk kinase) inhibitor PD98059 reduced expression of VCAM-1 after ICAM-1 cross-linking, suggesting that the Erk pathway is involved in ICAM-1-mediated VCAM-1 expression. In conclusion, ICAM-1-induced expression of VCAM-1 represents a pathway for adhesion molecule up-regulation that is distinct from the TNF-induced pathway. It may be similar to the IL-4 pathway or it may represent a novel pathway.
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PMID:Ligation of ICAM-1 on endothelial cells leads to expression of VCAM-1 via a nuclear factor-kappaB-independent mechanism. 1007 50

The adhesion molecule CD44 is a multifunctional, ubiquitously expressed glycoprotein that participates in the process of leukocyte recruitment to sites of inflammation and to their migration through lymphatic tissues. In this study, we have investigated the effect of the proinflammatory cytokine IL-1alpha on CD44 gene expression in the human immortalized endothelial cell line ECV304. Immunoblotting of cell extracts showed constitutive expression of a 85-kDa protein corresponding to the standard form of CD44, which was potently up-regulated following IL-1alpha treatment. Furthermore, IL-1alpha induced expression of v3- and v6-containing isoforms of CD44, which migrated at 110 and 140-180 kDa, respectively. The effect of IL-1alpha on CD44 standard, v3- and v6-containing isoforms was dose and time dependent and was inhibited in the presence of IL-1 receptor antagonist. To elucidate the molecular mechanisms regulating CD44 expression in response to IL-1alpha, we investigated the effect of IL-1alpha on CD44 mRNA expression. Reverse-transcriptase PCR and Northern analysis demonstrated an increase in CD44 mRNA expression indicating a transcriptional mechanism of control by IL-1alpha. Furthermore, IL-1alpha increased expression of a reporter gene under the control of the CD44 promoter (up to -1.75 kb). The effect of IL-1alpha was critically dependent on the site spanning -151 to -701 of the promoter. This effect required the presence of an Egr-1 motif at position -301 within the CD44 promoter since mutation of this site abolished responsiveness. IL-1alpha also induced Egr-1 expression in these cells. These studies therefore identify Egr-1 as a critical transcription factor involved in CD44 induction by IL-1alpha.
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PMID:Characterization of CD44 induction by IL-1: a critical role for Egr-1. 1020 38

We investigated the effect of antiretroviral therapy on vascular activation in 41 human immunodeficiency (HIV)--infected patients receiving a regimen that included either at least 1 protease inhibitor (PI; n = 21) or a nonnucleoside reverse-transcriptase inhibitor (NNRTI; n = 20). A control group of 21 healthy subjects was included for comparison. Levels of endothelial markers (soluble vascular cell adhesion molecule [sVCAM]--1, soluble intercellular adhesion molecule--1, and von Willebrand factor) were higher in HIV-infected persons before treatment than in control subjects and decreased significantly after 5--13 months of treatment. Levels of sVCAM-1 and von Willebrand factor correlated significantly with initial virus load. d-dimer concentrations also decreased significantly after initiation of treatment. PI- and NNRTI-containing regimens had similar effects. Therapy did not reduce levels of the soluble platelet (sP) activation markers sP-selectin and CD40 ligand. The inhibition of markers of vascular activation may counterbalance sequelae of therapy-induced dyslipidemia and potentially prevent development of atherosclerosis in HIV-infected patients.
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PMID:Antiretroviral therapy reduces markers of endothelial and coagulation activation in patients infected with human immunodeficiency virus type 1. 1186 97

Successful implantation is a highly coordinated process involving changes in cytokines, adhesion molecules, hormones, enzymes and growth factors. This study examines the expression of key cytokines and vascular surface molecules in the pregnant uterus of sheep around the time of implantation. Uterine tissues and uterine washings were collected from non-pregnant and pregnant sheep at 17-19 days post-coitus (dpc), 26-27 and 34-36 dpc. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of caruncular/placentomal tissues revealed that cytokines IL-2, IL-4 and IL-8, which were not detected in non-pregnant uterus, were induced more strongly at 26-27 dpc than at other stages of pregnancy tested. Cytokines LIF, IL-6, IL-10, TNF-alpha were also most highly expressed at 26-27 dpc, expression of them being lower at other time-points during early pregnancy and non-pregnancy. The cytokines IL-1beta, IFN-gamma and TGF-beta were expressed in all non-pregnant and pregnant tissues examined. Enzyme-linked immunosorbent assay (ELISA) performed on uterine washings clearly detected the presence of IL-1alpha protein at 26-27 and 34-36 dpc. Immunohistochemistry revealed that expression of vascular adhesion molecule VCAM-1 in endometrial endothelium was strongly induced at 26-27 dpc in the pregnant endometrium. Expression of CD5 on vascular endothelium was not induced in placentomal tissues until 26-27 dpc and was further increased by 34-36 dpc. These results demonstrate a dynamic change in a wide range of cytokines during early stages of pregnancy, with a critical period around 26-27 dpc. In addition, at 26-27 dpc, expression of the surface/adhesion molecules, CD5 and VCAM-1, is induced on vascular endothelium of the sheep endometrium, possibly as a direct consequence of the changed cytokine environment, and may be involved in directing the changes in leucocyte migration observed during pregnancy.
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PMID:Effects of implantation and early pregnancy on the expression of cytokines and vascular surface molecules in the sheep endometrium. 1559 26

ICAM-5 (telencephalin) is an intercellular adhesion molecule reported to be expressed only in the somatodendritic membrane of telencephalic neurons. We recently identified high ICAM-5 expression in a cDNA array study of head and neck neoplasms with a propensity for perineural invasion. To determine the association of this gene in tumorigenesis and perineural invasion, we analyzed the expression and functional status of ICAM-5 mRNA transcripts in 30 different human cancer cell lines and 25 head and neck squamous carcinoma specimens by reverse-transcriptase polymerase chain reaction (cell lines and specimens) and in vitro functional assays (cell lines). ICAM-5 transcripts were detected in 28 (93%) of 30 cell lines derived from primary head and neck, colon, thyroid, cervical, pancreatic, skin, and adenoid cystic carcinomas. In cell lines, small interfering RNA blocked ICAM-5 expression and inhibited cell proliferation. Treatment with the phosphatidylinositol 3'-kinase (PBK) inhibitor LY294002 resulted in ICAM-5 down-regulation. In tissue specimens, none of the 25 histologically normal oral mucosal specimens had detectable ICAM-5 level, whereas 16 (64%) of the 25 matched primary squamous carcinomas showed expression. Carcinoma specimens high ICAM-5 expression had a high incidence of perineural invasion. Our study indicates that ICAM-5 may play a role in tumorigenesis and perineural invasion, most likely through the P13K/Akt-signaling pathway.
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PMID:ICAM-5 (telencephalin) gene expression in head and neck squamous carcinoma tumorigenesis and perineural invasion! 1597 20


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