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:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1), gp160, is synthesized as a protein precursor that when proteolytically cleaved yields two subunits, gp120 and gp41. gp120 is the surface glycoprotein on HIV-1 responsible for binding to CD4, and gp41 is the transmembrane glycoprotein involved in the membrane fusion process. gp41 is divided into the N-terminal fusion peptide, the heptad repeat 1 (HR1) and HR2 regions, and the C-terminal transmembrane region, which are collectively responsible for virus fusion and entry into the cell. Synthetic peptides derived from the HR2 and HR1 regions of HIV-1(LAI) have been shown to prevent virus-cell fusion and infection in vitro. In phase II clinical trials in HIV patients, data revealed that T20 has antiviral efficacy and is well tolerated. Similar results were obtained in vitro with HIV-2 and simian immunodeficiency virus, supporting the conservation of the gp41 ectodomain among lentiviruses. Feline immunodeficiency virus (FIV) infection in the cat has been used as a model to develop potential antivirals for HIV. To determine if synthetic gp40 analogs capable of inhibiting FIV infection could be identified, 15 overlapping 35-amino-acid peptides derived from the C-terminal HR2 domain of FIV gp40 were synthesized. These peptides were tested for efficacy against FIV in a syncytium-forming assay with FIV-infected CrFK cells and HeLa cells expressing the FIV receptor CXCR4. Several peptides exhibited activity at the nanogram level. Antiviral activity was confirmed by suppression of reverse transcriptase in a FIV feline CD4(+)-T-cell (FCD4-E) acute-infection assay. These data demonstrate that synthetic peptides derived from the HR2 domain of the FIV gp41 protein are effective inhibitors of FIV infection.
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PMID:C-Terminal gp40 peptide analogs inhibit feline immunodeficiency virus: cell fusion and virus spread. 1218 91

Tissue factor (TF) is a transmembrane glycoprotein that initiates blood coagulation when complexed with factor (F)VIIa. Recently, TF has been shown to promote cellular signaling, tumor growth, angiogenesis, and metastasis. In the present study, we examined the pathway by which TF-FVIIa complex induces cellular signaling in human breast cancer cells using the Adr-MCF-7 cell line. This cell line has high endogenous TF expression as measured by flow cytometry and expression of protease-activated receptors 1 and 2 (PAR1 and PAR2) as determined by reverse transcriptase-polymerase chain reaction analysis. Both PAR1 and PAR2 are functionally active as determined by induction of p44/42 mitogen-activated protein kinase (MAPK) phosphorylation using specific agonist peptides. We found that MAPK phosphorylation in this cell line was strongly induced by the combination of FVIIa and factor (F)X, but not by FVIIa alone at a concentration of FVIIa that approaches physiological levels. Induction of MAPK phosphorylation involved the formation of TF-FVIIa-FXa complex and occurred by a pathway that did not require thrombin formation, indicating a critical role for FXa generation. In addition, induction of MAPK phosphorylation was found to be independent of PAR1 activation. We then examined whether TF-FVIIa complex formation could promote tumor cell migration using a modified Boyden chamber chemotaxis assay. The combination of FVIIa and FX, but not FVIIa alone, strongly induced migration of tumor cells by a pathway that probably involves PAR2, but not PAR1 activation. MAPK phosphorylation was found to be required for the induction of cell migration by the combination of FVIIa and FX. These data suggest that TF-FVIIa-mediated signaling in human breast cancer cells occurs most efficiently by formation of the TF-FVIIa-FXa complex. One of the physiological consequences of this signaling pathway is enhanced cell migration that is probably mediated by PAR2, but not PAR1 activation.
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PMID:Formation of tissue factor-factor VIIa-factor Xa complex promotes cellular signaling and migration of human breast cancer cells. 1471 72

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by the production of a broad spectrum of autoantibodies against nuclear, cytoplasmic and cell surface antigens and immune complex overload. Complement receptor 1 (CR1, CD 35), a transmembrane glycoprotein found on the surface of erythrocytes, leukocytes and glomerular podocytes plays a key role in the clearance of immune complexes and regulation of complement cascade. A drastic decline in the level of cell surface CR1 appears to be an important event in pathology of SLE. However, the etiology of lower than normal expression of cell surface CR1 in this disease is poorly understood. We studied the level of leukocyte CR1 transcription in 30 patients with active SLE and 30 controls by reverse transcriptase-polymerase chain reaction (RT-PCR) and related the same with the level of CR1 protein expression monitored by Western blotting. For RT-PCR, ratio of CR1/beta-actin was considered for semiquantitation of the level of CR1 transcription. Despite individual variation at the level of transcription, 70% (21 out of 30) of the patients expressed CR1 transcript at the lowest range of 0-15% as compared to the controls wherein only 30% (9 out of 30 individuals) demonstrated CR1 transcript in this range. Majority of the controls (70%) expressed CR1 transcript at the level above 15%. Mean level of CR1 transcript in patients (mean +/- S.D. = 21.09 +/- 14.3) was significantly lower than the controls (mean +/- S.D. = 48.91 +/- 26.34) (P < 0.001). The level of CR1 transcription correlated inversely with circulating immune complexes (CIC) (r = 0.52, P < 0.01). This may suggest that although erythrocyte CR1 is the chief vehicle for CIC clearance, drastic decline in leukocyte CR1 expression may impair the phagocyte mediated immune complex clearance and contribute to increased complement consumption in SLE. Total leukocyte CR1 protein expression was also significantly reduced in patients (P < 0.001) as compared to controls. This decline at the protein level gave a very significant positive correlation with CR1 transcript (r = 0.67, P < 0.01). A marginal increase in soluble CR1 (sCR1) was observed in the plasma (ELISA) of SLE patients compared to the controls but was insignificant. This paper for the first time brings evidence to suggest that reduced synthesis of CR1 contributes substantially to the low cell surface CR1 expression in SLE. Our findings also suggest increased proteolytic cleavage of leukocyte cell surface CR1 in these patients. However, evidence for the latter is indirect.
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PMID:Reduced complement receptor 1 (CR1, CD35) transcription in systemic lupus erythematosus. 1516 41

Despite a number of recent therapeutic advancements, there remains an urgent need to develop a new class of therapy for human immunodeficiency virus (HIV). This review summarises attempts at blocking HIV binding and entry into host cells, an approach that would provide theoretical advantages over the currently available drugs targeting enzymes (reverse transcriptase and protease), brought into play in the later stages of the viral life cycle. The multi-step process of HIV entry into cells, binding of the surface glycoprotein (gp120) to the CD4 receptor and one of the chemokine receptors, followed by the membrane fusion step mediated by the transmembrane glycoprotein (gp41), has recently been understood with greater clarity. The importance of the chemokine co-receptors, such as CCR5 and CXCR4, for HIV entry may help to explain the limitations of earlier approaches using recombinant soluble CD4 or polyanionic compounds to interfere non-specifically with HIV glycoprotein function. Conversely, previous investigations demonstrating the in vitro inhibitory potential of beta chemokines themselves, or small-molecule chemokine receptor inhibitors, may now be understood in a new light. Promising laboratory investigations (particularly with the bicyclam compound, AMD3100) and extensive pharmaceutical experience with related chemical structures suggest great potential for targeting the chemokine nexus. Finally, the evolution of transmembrane peptide investigations from the laboratory to early clinical trials is described. Clinical trials of T-20, a peptide designed to inhibit gp-41 mediated fusion, have provided 'proof of concept' that therapeutics targeting a viral entry event can result in safe and potent inhibition of viral replication. The author speculates on the future prospect of using novel therapeutic strategies aimed at the initial interactions between HIV and target cells, in the battle against AIDS.
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PMID:Therapeutic potential of blocking HIV entry into cells: focus on membrane fusion inhibitors. 1599 42

The myelin protein 0 (MPZ or P0) is a transmembrane glycoprotein that represents the most abundant myelin component. Mutations in the P0 gene are associated with one form of autosomal dominant demyelinating peripheral neuropathy, Charcot-Marie-Tooth disease type 1B (CMT1B). Because CMT1 may be associated with renal involvement, mostly focal segmental glomerulosclerosis, we hypothesized that P0 could be expressed in the kidney. P0 mRNA was detected by reverse transcriptase-PCR in the human and mouse renal cortex. P0 transcripts were identified by in situ hybridization at different stages of the mouse kidney development, especially in embryonic structures that give rise to the glomerulus. P0 protein was also detected by Western blot in human and rat glomerular extracts and in a human podocyte cell line using a monoclonal anti-P0 antibody. Immunofluorescence studies on human kidney sections showed that the podocytes were intensely labeled. Immunogold electron microscopy disclosed a predominant staining of the membranes of intracellular vesicles in podocytes. P0 was also detected in the podocyte cell membrane, including at the foot processes. P0(-/-) mice exhibited mild growth retardation and demyelinating neuropathy similar to the one observed in patients with CMT1B. They also presented mild albuminuria, without significant ultrastructural change of the glomerular basement membrane or the podocytes. These results demonstrate that P0, the major myelin protein, is also expressed during nephrogenesis and in mature kidney, mostly in podocytes. They suggest that P0 gene mutations might be involved in renal diseases.
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PMID:Glomerular permeability is altered by loss of P0, a myelin protein expressed in glomerular epithelial cells. 1616 11

The HIV replication cycle offers multiple targets for chemotherapeutic intervention, including the viral exterior envelope glycoprotein, gp120; viral co-receptors CXCR4 and CCR5; transmembrane glycoprotein, gp41; integrase; reverse transcriptase; protease and so on. Most currently used anti-HIV drugs are reverse transcriptase inhibitors or protease inhibitors. The expanding application of simulation to drug design combined with experimental techniques have developed a large amount of novel inhibitors that interact specifically with targets besides transcriptase and protease. This review presents details of the anti-HIV inhibitors discovered with computer-aided approaches and provides an overview of the recent five-year achievements in the treatment of HIV infection and the application of computational methods to current drug design.
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PMID:Therapeutic strategies underpinning the development of novel techniques for the treatment of HIV infection. 2009 4

CD147, a transmembrane glycoprotein member of the immunoglobulin superfamily of receptors, is involved in invasion and angiogenesis of some types of tumors; but its roles and clinicopathologic significance in pituitary adenomas are not clear. Using immunohistochemistry and quantitative reverse transcriptase polymerase chain reaction, we measured the expression of CD147, matrix metalloproteinase-2, and Ki-67 in 74 pituitary adenomas and evaluated the associations of CD147 with matrix metalloproteinase-2, Ki-67 labeling index, clinicopathologic characteristics, and prognosis. The CD147 protein was expressed in 35 (87.5%) of 40 invasive and in 16 (47.1%) of 34 noninvasive pituitary adenomas; and matrix metalloproteinase-2, in 32 (80.0%) and in 14 (41.2%) of 34, respectively. The Ki-67 labeling index was 3.93% +/- 2.48% for invasive samples and 1.32% +/- 1.04% for noninvasive ones. In addition, the expression of CD147 was positively correlated with matrix metalloproteinase-2, Ki-67 labeling index, or both in invasive pituitary adenomas (P< .01 and P< .01, respectively). All of the 4 recurrent adenomas were concurrently positive for CD147 and matrix metalloproteinase-2, and the Ki-67 labeling indexes of all were greater than 3%. Thus, CD147 may play a pivotal role in the development and progression of invasive pituitary adenomas and also be a useful prognostic biomarker.
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PMID:CD147 expression in pituitary adenomas and its significance for clinical outcome. 2038 Nov 19

The role of HIV-1-specific antibody responses in HIV disease progression is complex and would benefit from analysis techniques that examine clusterings of responses. Protein microarray platforms facilitate the simultaneous evaluation of numerous protein-specific antibody responses, though excessive data are cumbersome in analyses. Principal components analysis (PCA) reduces data dimensionality by generating fewer composite variables that maximally account for variance in a dataset. To identify clusters of antibody responses involved in disease control, we investigated the association of HIV-1-specific antibody responses by protein microarray, and assessed their association with disease progression using PCA in a nested cohort design. Associations observed among collections of antibody responses paralleled protein-specific responses. At baseline, greater antibody responses to the transmembrane glycoprotein (TM) and reverse transcriptase (RT) were associated with higher viral loads, while responses to the surface glycoprotein (SU), capsid (CA), matrix (MA), and integrase (IN) proteins were associated with lower viral loads. Over 12 months greater antibody responses were associated with smaller decreases in CD4 count (CA, MA, IN), and reduced likelihood of disease progression (CA, IN). PCA and protein microarray analyses highlighted a collection of HIV-specific antibody responses that together were associated with reduced disease progression, and may not have been identified by examining individual antibody responses. This technique may be useful to explore multifaceted host-disease interactions, such as HIV coinfections.
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PMID:Use of principal components analysis and protein microarray to explore the association of HIV-1-specific IgG responses with disease progression. 2413 21

Carcinoembryonic antigen-related adhesion molecule 1 (CEACAM1) is a type 1 transmembrane glycoprotein belonging to the CEA family, which has been found to exist as either soluble forms in body fluids or membrane-bound forms on the cell surface. Aberrant CEACAM1 expression is associated with tumor progression and has been found in a variety of human malignancies. Increasing interest has been devoted to the expression of CEACAM1 in breast cancer, but most of these findings are contradictory. The aim of this study was to investigate CEACAM1 expression in breast cancer in greater detail. Using immunohistochemical staining, we found that CEACAM1 expression was reduced or lost in breast cancer tissues compared with noncancerous breast tissues. In addition, soluble CEACAM1 levels in the culture medium of breast cancer cell lines were significantly lower than those in a nontumorigenic breast epithelial cell line. Immunofluorescence analysis consistently showed that breast cancer cell lines have relatively low expression of membrane-bound CEACAM1. Furthermore, CEACAM1 mRNA and protein expression levels were down-regulated in breast cancer cell lines as measured using real-time reverse transcriptase-polymerase chain reaction and western blot analysis, respectively. Taken together, our results demonstrate a systematic down-regulation of CEACAM1 in breast cancer and suggest that a strategy to restore CEACAM1 expression may be helpful for the treatment of breast cancer.
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PMID:Down-regulation of CEACAM1 in breast cancer. 2634 81


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