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 normal translocation of nascent polypeptides into the lumen of the endoplasmic reticulum (ER) is thought to be aided in part by a translocon-associated protein (TRAP) complex consisting of 4 protein subunits. The association of mature proteins with the ER and Golgi, or other intracellular locales, such as lysosomes, depends on the initial targeting of the nascent polypeptide to the ER membrane. A similar scenario must also exist for proteins destined for secretion. We have identified a member of the TRAP complex using a two hybrid screen to isolate proteins that bind to zebrafish (Danio) Ran binding protein 1. The polypeptide predicted from the largest open reading frame contains 183 amino acids with a 86 and 87% sequence identity to the TRAPbeta subunits in human and chicken, respectively. Sequence analysis identified a cleavable amino-terminal signal peptide in the zebrafish TRAPbeta subunit and a region of the protein spans the membrane of the endoplasmic reticulum. A reverse transcriptase-polymerase chain reaction assay showed that TRAPbeta mRNA is expressed in the developing zebrafish embryo. TRAPbeta mRNA is maternally supplied to the egg and is expressed constitutively throughout development and in the adult. This pattern of expression indicates that the message encoding part of the machinery targeting nascent polypeptides to the ER lumen is available at the onset of embryogenesis when the rate of translation increases exponentially over that occurring in the oocyte. In situ hybridization was used to test whether or not TRAPbeta transcripts might become localized and/or enriched in the developing embryo. Homogeneous staining is seen in the blastula and early gastrula stages. At mid-to-late gastrula stages, however, the message becomes enriched in the developing notochord and polster, or hatching gland rudiment. The TRAPbeta gene, mapped using the LN54 mouse-zebrafish radiation hybrid panel to linkage group 19, resides next to a gene (Z15451) which has sequence homology to notch2 and vascular endothelial growth factor. TRAPbeta, however, does not appear to belong to a group of genes which are syntenic with orthologues or paralogues on human chromosomes.
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PMID:The Translocon-Associated Protein beta (TRAPbeta) in zebrafish embryogenesis. I. Enhanced expression of transcripts in notochord and hatching gland precursors. 1120 60

Endothelin-1 (ET-1) has been shown to be mitogenic for endothelial and several tumor cells through an autocrine mechanism. In this study we evaluated whether the tumorigenic KS IMM cell line deriving from Kaposi's sarcoma (KS), a highly angiogenic tumor, is susceptible to ET-1 mitogenic activity. By reverse transcriptase-polymerase chain reaction, we detected ET-1 mRNA expression and both ET(A) receptor (ET(A)R) and ET(B)R mRNA transcripts in the KS IMM cells. High concentrations of ET-1 are released from the KS IMM cells and competition-binding studies demonstrated that these cells also express functional ET(A)R and ET(B)R with high affinity for ET-1 and ET-1/ET-3, respectively. Expression of ET-1 and cognate receptors could be detected by immunohistochemical method in vitro, in KS IMM xenograft, and in tissue sections of a human KS lesion. Furthermore ET-1 induces a marked and dose-dependent increase in [3H]thymidine incorporation comparable to that elicited by vascular endothelial growth factor. Addition of both selective ET(B)R antagonist (BQ 788) and ET(A)R antagonist (BQ 123), completely blocked ET-1-induced mitogenic response and reduced the basal growth rate of unstimulated cells, suggesting that both receptors mediated the proliferative signal. Such findings demonstrate that ET-1 participates on KS pathogenesis acting as an autocrine growth factor and that ET-1 receptor antagonists may thus be novel candidates for therapeutic intervention.
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PMID:Endothelin receptor blockade inhibits proliferation of Kaposi's sarcoma cells. 1123 33

Impaired wound healing is a well-documented phenomenon in experimental and clinical diabetes. Experimental evidence suggests that a defect in vascular endothelial growth factor (VEGF) regulation might be associated with wound-healing disorders. We studied the involvement of lipid peroxidation in the pathogenesis of altered VEGF expression in diabetes-related healing deficit by using an incisional skin-wound model produced on the back of female diabetic C57BL/KsJ db+/ db+ mice and their normal (db+/+m) littermates. Animals were then randomized to the following treatment: raxofelast (15 mg.kg(-1).day(-1) i.p.), an inhibitor of lipid peroxidation, or its vehicle (DMSO/NaCl 0.9%, 1:1 vol: vol). The animals were killed on different days (3, 6, and 12 days after skin injury), and the wounded skin tissues were used for histological evaluation, for analysis of conjugated dienes (CDs), as an index of lipid peroxidation and wound breaking strength. Furthermore, we studied the time course of VEGF mRNA expression throughout the skin-repair process (3, 6, and 12 days after skin injury), by means of reverse transcriptase-polymerase chain reaction, as well as the mature protein in the wounds. Diabetic mice showed impaired wound healing with delayed angiogenesis, low breaking strength, and increased wound CD content when compared with their normal littermates. In healthy control mice, a strong induction of VEGF mRNA was found between day 3 and day 6 after injury, while no significant VEGF mRNA expression was observed at day 12 after injury. In contrast, VEGF mRNA levels, after an initial increase (day 3), were significantly lower in diabetic mice than in normal littermates, and light induction of VEGF mRNA expression was also present at day 12 after injury. Similarly, the wound content of the angiogenic factor was markedly changed in diabetic mice. Administration of raxofelast did not modify the process of wound repair in normal mice, but significantly improved the impaired wound healing in diabetic mice through the stimulation of angiogenesis, re-epithelization, and synthesis and maturation of extracellular matrix. Moreover, raxofelast treatment significantly reduced wound CD levels and increased the breaking strength of the wound. Lastly, the inhibition of lipid peroxidation restored the defect in VEGF expression during the process of skin repair in diabetic mice and normalized the VEGF wound content. The current study provides evidence that lipid peroxidation inhibition restores wound healing to nearly normal levels in experimental diabetes-impaired wounds and normalizes the defect in VEGF regulation associated with diabetes-induced skin-repair disorders.
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PMID:Inhibition of lipid peroxidation restores impaired vascular endothelial growth factor expression and stimulates wound healing and angiogenesis in the genetically diabetic mouse. 1124 89

We studied expressions of various growth factors, their receptors, cell adhesion molecules and extracellular matrix components in Warthin's tumor of the salivary gland with immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR). Various growth factors and their receptors, such as transforming growth factor-alpha (TGF-alpha), heparin-binding epidermal growth factor-like growth factor (HB-EGF), TGF-beta2, TG-beta3, insulin-like growth factor (IGF)-I and -II, vascular endothelial growth factor (VEGF), EGF receptor (EGFR), erb-B4, TGF-betaRI and II, Flt and Flk-1 and IGF receptor Ibeta, were found in epithelial cells and/or in some lymphoid cells. Fibronectin, laminin, collagen type IV and tenascin were found in stroma of the lymphoid tissue. Integrins such as alpha3beta1 and beta3, Thy-1, CD44 and VCAM-1 were also expressed in epithelial and/or lymphoid cells. These various proteins may interact and regulate the proliferation and cell attachment of both epithelial and lymphoid components in this unique tumor.
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PMID:Growth factors, extracellular matrix components and cell adhesion molecules Warthin's tumor. 1133 65

In highly vascular malignant glioma, glioma cells themselves may express angiogenic factors and induce angiogenesis. Recent studies have shown that novel angiogenic factors, angiopoietin-1 (Ang1) and -2 (Ang2), play important roles in the modulation of vasculogenesis and angiogenesis. In this study, we determined Ang2 mRNA expression in cultured human malignant glioma cells (U105, U251, and U373 MG) by reverse transcriptase-PCR. Western blot analysis and immunocytochemical analysis with antihuman Ang2 antibody revealed that Ang2 protein was expressed and secreted by these cells. Furthermore, hypoxia increased the Ang2 protein level in cultured glioma cells. Serial sections of 32 human glioma tissues (14 glioblastomas, eight anaplastic astrocytomas, seven astrocytomas, and three pilocytic astrocytomas) were immunostained against Ang2, vascular endothelial growth factor, Tie2, von Willebrand factor, and alpha smooth muscle actin. The immunoreactivity of each angiogenic factor was higher in malignant gliomas than in low-grade gliomas. Ang2 protein was detected not only in endothelial cells but also in glioma cells, and its expression was prominent in both the area surrounding the necrosis and the periphery of glioblastomas. In the area surrounding necrosis, Ang2 was highly expressed and tumor vessels showed regression. In the tumor periphery, Ang2 was highly expressed and many small vessels stained positively for von Willebrand factor but not for alpha smooth muscle actin, suggesting angiogenesis. Statistical analysis revealed that the Ang2 expression was negatively correlated with vessel maturation in malignant gliomas and that vascular endothelial growth factor expression was positively correlated with vessel maturation in low-grade gliomas (P < 0.05). These results suggest that glioma cells themselves express Ang2 and that expression may be induced by hypoxic stimulation and may play a crucial role in the vessel maturation, angiogenesis, and vessel regression in malignant glioma.
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PMID:Expression of angiopoietin-2 in human glioma cells and its role for angiogenesis. 1150 79

Hereditary paragangliomas are usually benign tumors of the autonomic nervous system that are composed of cells derived from the primitive neural crest. Even though three genes (SDHD, SDHC, and SDHB), which encode three protein subunits of cytochrome b of complex II in the mitochondrial respiratory chain, have been identified, the molecular mechanisms leading to tumorigenesis are unknown. We studied a family in which the father and his eldest son had bilateral neck paragangliomas, whereas the second son had a left carotid-body paraganglioma and an ectopic mediastinal pheochromocytoma. A nonsense mutation (R22X) in the SDHD gene was found in these three affected subjects. Loss of heterozygosity was observed for the maternal chromosome 11q21-q25 within the tumor but not in peripheral leukocytes. Assessment of the activity of respiratory-chain enzymes showed a complete and selective loss of complex II enzymatic activity in the inherited pheochromocytoma, that was not detected in six sporadic pheochromocytomas. In situ hybridization and immunohistochemistry experiments showed a high level of expression of markers of the angiogenic pathway. Real-time quantitative reverse transcriptase (RT)-PCR measurements confirmed that vascular endothelial growth factor and endothelial PAS domain protein 1 mRNA levels were significantly higher (three- and sixfold, respectively) than those observed in three sporadic benign pheochromocytomas. Thus, inactivation of the SDHD gene in hereditary paraganglioma is associated with a complete loss of mitochondrial complex II activity and with a high expression of angiogenic factors.
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PMID:The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. 1160 59

The effects of exogenous vascular endothelial growth factor (VEGF) on angiogenesis, blood-brain barrier permeability and astroglial proliferation in the adult rat CNS in situ were investigated. Recombinant human VEGF(165) (25 or 50 ng/ml) was delivered for up to 1 week using either intracerebral osmotic minipumps or less traumatic subdural gelatin sponge placement. By 3 days, VEGF delivery caused significantly increased cerebral angiogenesis (25 ng/ml was most effective) in both experimental models when compared to saline controls; VEGF infusion resulted in a 100% increase in an index of vascular proliferation, and gelatin sponge delivery produced a 65% increase. The blood-brain barrier hallmark endothelial glucose transporter-1 was not present in nascent vascular sprouts. Infusion of VEGF produced extensive protein leakage that persisted after saline-induced permeability was mostly resolved, while gelatin sponge administration caused milder barrier dysfunction. Administration of the angiogenic factor had unexpected proliferative effects on astroglia in both models, resulting in an 80-85% increase in mitotically active astroglia when compared to controls. Immunohistochemical results and semi-quantitative reverse transcriptase-polymerase chain reaction indicated that the VEGF receptors flk-1 and flt-1 were up-regulated in response to the infusion trauma; flt-1 was localized to reactive astroglia, while flk-1 was expressed in vascular endothelium but predominantly in neuronal somata and processes adjacent to the delivery site. mRNA for the VEGF(121), VEGF(165) and VEGF(188) isoforms was also increased after delivery of the recombinant protein. These data show that VEGF application has substantial proliferative effects on CNS endothelium and astroglia and causes up-regulation of its own message. Flt-1 and flk-1 receptor mRNAs and proteins are up-regulated in both vascular and non-vascular cell types following infusion trauma. From these results we suggest that administered VEGF has heretofore unanticipated pleiotrophic effects in the adult CNS.
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PMID:Angiogenic and astroglial responses to vascular endothelial growth factor administration in adult rat brain. 1193 68

Inflammatory breast cancer (IBC) is a specific type of breast tumor that generally has a poor prognosis, in spite of recent advances in treatment. In the present study, semiquantitative reverse transcriptase polymerase chain reaction examination of resected specimens showed that angiogenic factors, not lymphangiogenic factors, are overexpressed in IBC tumors, compared with non-IBC tumors. Immunohistochemical analysis of the specimens revealed a significantly higher population of tumor-infiltrating (TI) endothelial cells (ECs) or endothelial precursor cells (EPCs) in tumor-associated stroma of IBC specimens than in non-IBC specimens. In a previous study, we examined the phenotype of host cells in response to transplanted IBC cells, using an established human IBC xenograft model (WIBC-9) (Shirakawa et al., Cancer Res 2001;61:445-51). The data obtained in that study are consistent with the findings of the present study. To explore the therapeutic potential of blocking vascular endothelial growth factor (VEGF) and angiopoietin (Ang) pathways in IBC, established vectors encoding soluble Flt-1 (sFlt-1) and soluble Tie2 (sTie2) were injected directly into WIBC-9. Both vectors produced growth inhibition ratios of WIBC-9 that were significantly higher than those of a non-IBC xenograft (MC-5). Also, both vectors suppressed WIBC-9 lung metastases. The efficacy correlated with the number of TI ECs/EPCs, which was determined by fluorescence-activated cell sorting. These ECs/EPCs incorporated acetylated lipoprotein and were integrated within a HUVEC monolayer in vitro culture on day 5.
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PMID:Tumor-infiltrating endothelial cells and endothelial precursor cells in inflammatory breast cancer. 1199 2

Angiogenesis is a prominent feature of glioblastomas but the mechanisms involved in the control of this process are poorly understood. We have investigated the potential role of a recently described transcription factor, hypoxia-inducible factor 1 (HIF-1), which initiates the transcription of a number of hypoxia-inducible genes, including those encoding vascular endothelial growth factor and its receptors. HIF-1 protein expression was assessed by immunocytochemistry, using a monoclonal antibody to the alpha subunit (HIF-1alpha). HIF-1 mRNA expression was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) and the ribonuclease protection assay (RPA). Strong nuclear expression of HIF-1alpha protein was seen in the majority of glioblastomas and anaplastic astrocytomas, particularly surrounding areas of necrosis in glioblastomas. In the majority of these tumours upregulation of HIF-1alpha mRNA was also demonstrated, with a significant increase in glioblastomas compared to lower grade tumours. No correlation was found between the presence of HIF-1alpha protein and immunohistochemical expression of p53 protein. These findings are in keeping with an important role of HIF-1alpha in the vascularization of glioblastomas and suggest that upregulation is at least partly at a transcriptional level.
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PMID:Expression of hypoxia-inducible factor 1alpha in tumours of patients with glioblastoma. 1206 Mar 45

We examined the relationship between vascular endothelial growth factor (VEGF)-C expression and lymph node metastases in gastric carcinomas invading the submucosa. Of the six human gastric carcinoma cell lines, two constitutively expressed VEGF-C mRNA. In three of 12 gastric biopsy specimens (25%), VEGF-C mRNA was detected in tumour tissues, but not in corresponding normal mucosa by reverse transcriptase-polymerase chain reaction (RT-PCR). Of the 139 resected gastric carcinomas, 44 (32%) showed intense cytoplasmic VEGF-C immunoreactivity in many cancer cells at the invading edge. VEGF-C immunoreactivity was associated with greater depth of tumour invasion, lymphatic invasion and lymph node metastases. In addition, vessel count was also significantly higher in the VEGF-C immunoreactive tumours than in other tumours. These results suggest that VEGF-C may be involved in the progression of human gastric carcinoma, particularly via lymphangiogenesis. VEGF-C expression at the invading edge of a gastric carcinoma may be a sensitive marker for metastasis to the lymph nodes.
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PMID:Vascular endothelial growth factor-C expression predicts lymph node metastasis of human gastric carcinomas invading the submucosa. 1209 Oct 74


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