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

We have identified Celsr1, a gene that encodes a developmentally regulated vertebrate seven-pass transmembrane protein. The extracellular domain of Celsr1 contains two regions each with homology to distinct classes of well-characterized motifs found in the extra-cellular domains of many cell surface molecules. The most N-terminal region contains a block of contiguous cadherin repeats, and C-terminal to this is a region containing seven epidermal growth factor-like repeats interrupted by two laminin A G-type repeats. Celsr1 is unique in that it contains this combination of repeats coupled to a seven-pass transmembrane domain. As part of the characterization of the Celsr1 gene, we have determined its chromosomal map location in both mouse and human. The European Collaborative Interspecific Backcross (EUCIB) and BXD recombinant inbred strains were used for mapping Celsr1 cDNA clones in the mouse, and fluorescence in situ hybridization was used to map human Celsr1 cosmid clones on metaphase chromosomes. We report that Celsr1 maps to proximal mouse Chromosome 15 and human chromosome 22qter, a region of conserved synteny. Reverse transcriptase-polymerase chain reaction analysis and in situ hybridization were used to determine the spatial restriction of Celsr1 transcripts in adult and embryonic mice. The results presented here extend our previous finding of expression of the Celsr1 receptor in the embryo and show that expression continues into adult life when expression in the brain is localized principally in the ependymal cell layer, choroid plexus, and the area postrema.
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PMID:Celsr1, a neural-specific gene encoding an unusual seven-pass transmembrane receptor, maps to mouse chromosome 15 and human chromosome 22qter. 933 65

Growth factors and prostaglandins protect the gastric mucosa against stress-induced lesions but their role in the recovery of the mucosa from these lesions has been little studied. We evaluated gastric mucosa lesions, gastric blood flow, mucosal generation of prostaglandin E2 and mucosal gene expression of epidermal growth factor (EGF) and transforming growth factor alpha (TGF alpha) as well as constitutive prostaglandin cyclooxygenase-1 and inducible cyclooxygenase-2 and the effect of the inhibition of these enzymes on the recovery of mucosa from the stress-induced lesions. Rats were exposed to 3.5 h of water immersion and restraint stress and killed at 0, 2, 4, 6, 8, 12 and 24 h after stress. The number of gastric lesions was determined and gastric blood flow was measured by H2-gas clearance. Gastric acid secretion was tested in separate gastric fistula rats. Gastric mucosa biopsies were taken for determination of immunoreactive EGF and TGF alpha. Expression of EGF and TGF alpha mRNA and cyclooxygenase-1 and cyclooxygenase-2 mRNA was also determined by reverse-transcriptase polymerase chain reaction. The number of gastric lesions induced by 3.5 h stress averaged approximately 20 per rat and declined significantly at 2, 4, 6, 8 and 12 h, to disappear almost completely after 24 h. This was accompanied by a gradual rise in gastric blood flow, mucosal generation of prostaglandin E2 and mucosal EGF and TGF alpha contents, while the increased gastric acid secretion returned to normal. In the intact mucosa, EGF mRNA was not detected but TGF alpha mRNA was found in measurable amounts. Following exposure to stress, the expression of both these factors was significantly increased. Similarly, the expression of cyclo-oxygenase-1 and cyclooxygenase-2 mRNA was detected in the oxyntic mucosa at all time intervals after exposure to stress. Indomethacin (5 mg/kg i.p.), an inhibitor of cyclooxygenase-1 and cyclooxygenase-2, and meloxicam (1 mg/kg i.p.), an inhibitor of cyclooxygenase-2, both prolonged the healing of stress lesions and reduced the gastric blood flow, while enhancing gastric acid secretion at all times tested. We conclude that healing of stress lesions results in the restoration gastric blood flow and mucosal prostaglandin generation and that these effects are accompanied by overexpression of EGF and TGF alpha as well as cyclooxygenase-1 and cyclooxygenase-2 mRNA and by increased biosynthesis of gastroprotective prostaglandin.
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PMID:Activation of genes for growth factors and cyclooxygenases in rat gastric mucosa during recovery from stress damage. 954 93

Polyamines such as spermine or putrescine, resulting from increased activity of ornithine decarboxylase (ODC), are known for gastroprotective and mucosal growth promoting effects but little information is available about their role in the acceleration of the healing of stress-induced gastric lesions by epidermal growth factor (EGF). In this study, rats with intact or suppressed ODC activity by alpha-difluoromethylornithine (DFMO, 400 mg/kg i.p.) were subjected to 3.5 h of water immersion and restraint stress (WRS) without or with intragastric (i.g.) administration of spermine and putrescine or with subcutaneous (s.c.) injection of EGF. At 0, 2, 6, 12 and 24 h after stress, rats were killed and the number of gastric lesions was counted, gastric blood flow (GBF) was recorded by the H2-gas clearance technique, the gene expression of ODC mRNA using reverse-transcriptase polymerase chain reaction (RT-PCR) and the ODC activity in this mucosa were determined in oxyntic mucosa. Stress produced gastric lesions combined with decreased GBF (by approximately 43%), but at 2, 6, 12 and 24 h after stress, these lesions and the fall in GBF were gradually attenuated. Healing of stress lesions was accompanied by strong stimulation of ODC mRNA expression and by an immediate increase in enzyme activity, with a peak occurring about 6 h after stress. Pretreatment with DFMO or salivectomy (which resulted in a marked fall in luminal EGF levels and mucosal DNA synthesis) delayed significantly the healing of stress lesions. EGF or spermine significantly accelerated the ulcer healing and raised the GBF. Suppression of endogenous generation of prostaglandins (PGs) with indomethacin (5 mg/kg i.p.) almost completely reversed the EGF- and spermine-induced acceleration of the healing of stress lesions and the accompanying rise in GBF. DFMO significantly reduced the enhancement in healing and the rise in the GBF induced by EGF, but failed to influence those induced by exogenous spermine. The acceleration of the healing induced by spermine or EGF and accompanying hyperemia were not affected by salivectomy. We conclude that (1) upregulation of the ODC transcript, increased ODC activity and polyamines play an important role in mucosal recovery from stress lesions due to acceleration of mucosal repair and an increase in gastric microcirculation, (2) increased ODC activity and resulting excessive polyamine release appear to act as primary mediators of EGF-induced acceleration of healing of stress lesions and (3) endogenous PGs cooperate with EGF and polyamines in mucosal repair from stress ulcerations.
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PMID:Involvement of ornithine decarboxylase and polyamines in epidermal growth factor-induced recovery of gastric mucosa from gastric lesions provoked by stress. 971 66

Expression of mRNA for heregulin (HRG), a member of the epidermal growth factor (EGF) family and its receptors, ErbB-3 and ErbB-4, were evaluated in human upper gastrointestinal (GI) mucosa. Multi-target reverse-transcriptase polymerase chain reaction (RT-PCR) analysis using capillary electrophoresis and laser-induced fluorescence allowed us to quantify the minute amounts of mRNA from one biopsy specimen with high sensitivity. HRG, ErbB-3 and ErbB-4 mRNA were detected in esophagus, stomach and duodenum and the highest expression was found in duodenum. In gastric cancer, mRNA for ErbB-4 was significantly overexpressed. Immunoreactivity of ErbB-4 in carcinoma cell membrane was also confirmed. These findings suggest that HRG and its receptors, ErbB-3 and ErbB-4 may be physiologically significant in the human upper GI mucosa, especially in duodenum, and that ErbB-4 may contribute to the growth of gastric cancer.
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PMID:Expression of mRNA for heregulin and its receptor, ErbB-3 and ErbB-4, in human upper gastrointestinal mucosa. 971 81

To identify extracellular proteins with epidermal growth factor (EGF) domains that are potentially involved in the control of haemopoiesis, we performed degenerate reverse-transcriptase-mediated PCR on the murine bone-marrow stromal cell line MS-5 and isolated a new partial cDNA encoding EGF-like domains related to those in the Notch proteins. Cloning and sequencing of the full-length cDNA showed that it encoded a new extracellular multi-domain protein that we named polydom. This 387 kDa mosaic protein contained a signal peptide followed by a new association of eight different protein domains, including a pentraxin domain and a von Willebrand factor type A domain, ten EGF domains, and 34 complement control protein modules. The human polydom mRNA is strongly expressed in placenta, its expression in the other tissues being weak or undetectable. The particular multidomain structure of the encoded protein suggests an important biological role in cellular adhesion and/or in the immune system.
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PMID:Polydom: a secreted protein with pentraxin, complement control protein, epidermal growth factor and von Willebrand factor A domains. 1106 57

Leptin was shown to exhibit similar to cholecystokinin (CCK) cytoprotective activity against acute gastric lesions, but its role in ulcer healing has not been examined. The aims of this study were: (1) to compare the effects of exogenous leptin to those of CCK on the course of healing of chronic gastric ulcers; (2) to study the gene and protein expression of leptin at the ulcer margin during ulcer healing; and (3) to assess the effects of leptin administration on the mucosal gene expression of main growth factor such as transforming growth factor alpha (TGFalpha). Gastric ulcers were produced in rats by the acetic acid method. Rats with ulcers were divided in following treatment groups: (1) vehicle; (2) leptin (10 microg/kg i.p.); (3) CCK (10 microg/kg s.c.); and (4) leptin or CCK with or without tyrphostin A46 (200 microg/kg i.p.), an inhibitor of epidermal growth factor (EGF)-receptor tyrosine kinase or NG-nitro-L-arginine (20 mg/kg i.g.), a blocker of nitric oxide synthase. Animals were euthanized 9 days after ulcer induction. The area of gastric ulcers and the gastric blood flow at the ulcer area were determined. In addition, mucosal biopsy samples were taken from the ulcer area for histological evaluation as well as for the determination of mRNA and protein expression for leptin and constitutive nitric oxide synthase (cNOS) and inducibile nitric oxide synthase (iNOS) by reverse-transcriptase polymerase chain reaction (RT-PCR) and Western blot, respectively. In addition, the gene expression for TGFalpha was analyzed by RT-PCR. Both leptin and CCK reduced significantly the ulcer area as compared to vehicle-treated group by approximately 50%. The treatment with tyrphostin or N(G)-nitro-L-arginine reversed in part the acceleration of ulcer healing by leptin and CCK. The expression of leptin mRNA and protein was significantly increased at the ulcer edge. The leptin-induced acceleration of ulcer healing was associated with increased expression of transcripts for TGFalpha as well as increased mRNA and protein expression for cNOS and iNOS at the ulcer margin. We conclude that leptin accelerates ulcer healing by mechanisms involving the up-regulation of TGFalpha and increased production of nitric oxide due to up-regulation of cNOS and iNOS in the ulcer area.
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PMID:Role of leptin in ulcer healing. 1123 Sep 99

Hyaluronan is an abundant and rapidly turned over matrix molecule between the vital cell layers of the epidermis. In this study, epidermal growth factor (EGF) induced a coat of hyaluronan and a 3-5-fold increase in its rate of synthesis in a rat epidermal keratinocyte cell line that has retained its ability for differentiation. EGF also increased hyaluronan in perinuclear vesicles, suggesting concurrent enhancement in its endocytosis. Cell-associated hyaluronan was most abundant in elongated cells that were stimulated to migrate by EGF, as determined in vitro in a wound healing assay. Large fluctuations in the pool size of UDP-N-acetylglucosamine, the metabolic precursor of hyaluronan, correlated with medium glucose concentrations but not with EGF. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed no increase in hyaluronan synthases 1 and 3 (Has1 and Has3), whereas Has2 mRNA increased 2-3-fold in less than 2 h following the introduction of EGF, as estimated by quantitative RT-PCR with a truncated Has2 mRNA internal standard. The average level of Has2 mRNA increased from approximately 6 copies/cell in cultures before change of fresh medium, up to approximately 54 copies/cell after 6 h in EGF-containing medium. A control medium with 10% serum caused a maximum level of approximately 21 copies/cell at 6 h. The change in the Has2 mRNA levels and the stimulation of hyaluronan synthesis followed a similar temporal pattern, reaching a maximum level at 6 h and declining toward 24 h, a finding in line with a predominantly Has2-dependent hyaluronan synthesis and its transcriptional regulation.
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PMID:Epidermal growth factor activates hyaluronan synthase 2 in epidermal keratinocytes and increases pericellular and intracellular hyaluronan. 1126 89

The lipoxygenase pathway has been implicated in the growth, migration, and contraction of vascular smooth muscle cells (VSMCs). However, the precise type of lipoxygenase present in the vascular wall has not been characterized. In this study, we used a specific reverse-transcriptase polymerase chain reaction method with 2 sets of specific primers on total RNA and polyA (+)RNA of normal human VSMCs prepared from umbilical artery. Two forms of platelet-type 12-lipoxygenase mRNA were present in human VSMCs: the already published form cloned from human erythroleukemia cells and a variant form of platelet-type 12-lipoxygenase, which includes 2 additional sequences consistent with the 2 introns (D and E). This novel form of 12-lipoxygenase poly A (+)RNA was downregulated by lipopolysaccharide (10 ug/ml) and upregulated by epidermal growth factor (100 ng/ml) but was not affected by angiotensin II (10(-7) mol/l). We developed a rabbit anti-human platelet-type 12-lipoxygenase polyclonal antibody directed against a 24-amino acid peptide encoded within exon 4. Western immunoblotting of protein extracted from VSMCs and umbilical artery and platelet extract with this antibody showed a coordinate 110-kDa protein and the already-described 70-kDa band detected in platelets and cord homogenate. Another 120-kDa protein was consistently detected in cord extracts but not in platelet or VSMC homogenates. The immunohistochemistry study performed with the same antibody showed extensive cytoplasmic staining of VSMCs. The specific role of these different forms of platelet-type 12-lipoxygenase is subject to further investigation.
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PMID:A novel form of platelet-type 12-lipoxygenase mRNA in human vascular smooth muscle cells. 1164

The Achilles tendon is one of the most common sites of injury and rupture. Evidence suggests that local vascularisation is involved in this aetiology. We investigated the expression of one important angiogenic factor, the vascular endothelial growth factor (VEGF), in normal and pathologic human Achilles tendons using immunohistochemical, biochemical, molecular and cell biology methods. VEGF could be immunostained in tenocytes of ruptured and foetal Achilles tendons, but not in normal adult ones. In microvessels, the VEGF receptor VEGFR-1 (flt-1) could be visualised as well. High VEGF levels were measured in homogenates from ruptured adult, lower ones in foetal and negligible concentrations in normal adult Achilles tendons using enzyme-linked immunoassay (ELISA) and Western blot experiments. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed that the splice variants VEGF121 and VEGF165 are exclusively expressed. In tenocytes cultivated from newborn rat Achilles tendons, hypoxia or epidermal growth factor (EGF) raised VEGF production moderately whereas their combination resulted in a strong, synergistic induction. These results prove the presence of an angiogenic peptide and vascularisation in ruptured and foetal tendons and support the view that microtrauma or degeneration in the Achilles tendon precedes its rupture.
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PMID:The angiogenic peptide vascular endothelial growth factor is expressed in foetal and ruptured tendons. 1171 Jun 46

We have cloned the cDNAs of the zebrafish (Danio rerio) members of the matrilin family of extracellular adaptor proteins. In contrast to mammals, no orthologue of matrilin-2 was found in zebrafish, either by RT (reverse-transcriptase) PCR using degenerated primers or by screening the databases (Ensembl and NCBI); however, two forms of matrilin-3, matrilin-3a and -3b, were present. The identity with the mammalian matrilins is from more than 70% for the VWA (von Willebrand factor A)-like domains to only 28% for the coiled-coil domains of matrilin-3a and -3b. In all zebrafish matrilins we found a greater variety of splice variants than in mammals, with splicing mainly affecting the number of EGF (epidermal growth factor)-like repeats. The exon-intron organization is nearly identical with that of mammals, and also the characteristic AT-AC intron interrupting the exons coding for the coiled-coil domain is conserved. In the matrilin-3b gene a unique exon codes for a proline- and serine/threonine-rich domain, possibly having mucin-like properties. The matrilin-1 and -3a genes were mapped to chromosome 19 and 20 respectively by the radiation hybrid method. The temporal and spatial expression of zebrafish matrilins is similar to that seen in the mouse. Zebrafish matrilin-4 is highly expressed as early as 24 hpf (h post fertilization), whereas the other matrilins show peak expression at 72 hpf. By immunostaining of whole mounts and sections, we found that matrilin-1 and -3a show predominantly skeletal staining, whereas matrilin-4 is more widespread, with the protein also being present in loose connective tissues and epithelia.
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PMID:Zebrafish (Danio rerio) matrilins: shared and divergent characteristics with their mammalian counterparts. 1558 28


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