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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Late radiation-induced changes in transforming growth factor beta (TGF-beta), collagen I and collagen III content of the bladder wall, as well as morphological alterations of the uroepithelium, were analyzed quantitatively in an immunohistochemical study. An interlaboratory, i.e. interstrain, comparison of two mouse strains (Amsterdam C3H/Hen Af-nu+ and Munich C3H Neu) with different dose-effect relationships for late bladder damage was made, choosing radiation doses producing equivalent functional alterations in both strains (ED80 of 25 Gy and 19 Gy, respectively, 40 weeks after irradiation). In one strain of mouse, cystometry was also performed in the same animals at different times after irradiation. The TGF-beta staining intensity showed a progressive increase between 90 and 360 days after irradiation. This increase was similar in both strains of mouse treated with functionally equivalent doses (ED80) and was less pronounced after a lower, ED40, dose in the Munich mice. In both strains, there was a radiation-induced increase in both collagen subtypes from 180 days after irradiation with the ED80. The ratio of collagen type I/III, however, decreased in the Amsterdam mice and increased in the Munich mice. The relative radioresistance of the Amsterdam mice may therefore be partly due to a greater contribution of the elastic collagen type III, affording greater bladder compliance after irradiation. The extent of radiation-induced uroepithelial denudations or papillomatous outgrowths, the TGF-beta staining intensity and collagen I/III ratio were each correlated to bladder function determined by cystometry for the Munich mice. This correlation was statistically significant for all three parameters for group mean responses and, with the exception of the collagen I/III ratio, also for individual mice. These experiments indicate that chronic radiation-induced alterations in TGF-beta expression and connective tissue metabolism in the bladder wall are possibly important factors determining reduced bladder function after irradiation.
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PMID:Radiation-induced changes in transforming growth factor beta and collagen expression in the murine bladder wall and its correlation with bladder function. 895 11

The process of corneal wound healing involves the transformation of adjacent corneal keratocytes to myofibroblast-like cells characterized by the development of prominent microfilament bundles containing alpha-smooth muscle-specific actin (alpha-SM), a contractile protein thought to be important in mediating wound contraction. Recent studies have shown that the expression of alpha-SM in cultured corneal keratocytes can be induced by serum and TGF beta 1. To study the cellular and molecular mechanisms underlying this transformation process and to begin to identify the role of alpha-SM in wound contractile events, we generated immortalized rabbit corneal cell strains with extended life by using SV40 transfection. Two unique strains were isolated (TRK-36 and TRK-43). TRK-36, which appears similar to normal corneal keratocytes, maintains a stellate, keratocyte morphology when grown in the absence of serum and transforms to a myofibroblast-like cell when treated with TGF beta 1 (1 ng/ml), as indicated by the induced expression of alpha-SM actin. TRK-43 exhibits features characteristic of myofibroblasts in that it constitutively expresses alpha-SM actin under serum-free conditions. Both strains show in vitro contraction of collagen gels < or = 80% in 24 h in serum-containing medium. Interestingly, under serum-free conditions, TRK-43 cells showed significantly greater contraction of collagen gels compared with those of TRK-36. Overall, the establishment and further study of these cell strains may provide important insights into the molecular mechanisms underlying myofibroblast transformation.
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PMID:Characterization of SV40-transfected cell strains from rabbit keratocytes. 898 37

Hepatocyte growth factor (HGF)/scatter factor (SF) is the ligand for a tyrosine kinase cell surface receptor encoded by the MET protooncogene (c-MET). HGF/SF can induce proliferation and motility in epithelial cells and promotes invasion of carcinoma cells and NIH3T3 fibroblasts transfected with both HGF/SF and c-MET genes. Our results show that HGF/ SF and c-MET also play a role in adhesion and invasion of human lymphoma cells. c-MET mRNA is expressed in hemopoietic cells, such as hemopoietic progenitor cells (CD34+ cells) in bone marrow (BM) and mobilized peripheral blood, immature B cells in cord blood and BM, and germinal center B-centroblasts. In normal peripheral blood B cells, which are c-MET-, c-MET expression was induced by PMA, ConA, HGF/ SF, and Epstein-Barr virus (EBV) infection. Using immunohistochemistry, we detected c-MET on the cell surface of large activated centroblasts in lymph nodes from patients with B-non-Hodgkin's lymphoma and Hodgkin's disease. In the latter group, c-MET expression correlated well with the presence of EBV. Because HGF/SF and c-MET promote metastasis of carcinoma cells, we studied the effects of c-MET stimulation by HGF/SF of B-lymphoma cells on properties relevant for metastasis, ie, adhesion, migration, and invasion. HGF/SF stimulated adhesion of the c-MET+ B-cell lines to the extracellular matrix molecules fibronectin (FN) and collagen (CN) in a dose dependent manner. However, adhesion to laminin was not affected by HGF/SF. Adhesion to FN was mediated by beta 1-integrins alpha 4 beta 1 (VLA4) and alpha 5 beta 1 (VLA5) since blocking antibodies against beta 1- (CD29), alpha 4-(CD49d), or alpha 5- (CD49e) integrin subunits, completely reversed the effect of HGF/SF. Furthermore, HGF/SF induced adhesion was abrogated by addition of genistein, which blocks protein tyrosine kinases, including c-MET. Addition of HGF/SF resulted in a sixfold increase in migration of c-MET B-lymphoma cells through Matrigel, compared to medium alone. In rat fibroblast cultures, HGF/SF doubled the number of c-MET+ B-lymphoma cells that invaded the fibroblast monolayer. In these adhesion, migration and invasion assays HGF/SF had no effect on c-MET- cell lines. In conclusion, c-MET is expressed or can be induced on immature, activated, and certain malignant B cells. HGF/SF increased adhesion of c-MET+ B-lymphoma cells to FN and CN, mediated via beta 1-integrins alpha 4 beta 1 and alpha 5 beta 1, and furthermore promoted migration and invasion.
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PMID:Hepatocyte growth factor/scatter factor promotes adhesion of lymphoma cells to extracellular matrix molecules via alpha 4 beta 1 and alpha 5 beta 1 integrins. 902 31

Because of its chemical versatility and demonstrated biocompatibility, poly(2-hydroxyethyl methacrylate) (pHEMA) has been widely used as a polymer for biomedical applications. Since this hydrophilic material shows a poor interface with cells, blendings with other polymers were done to improve cytocompatibility. In our polymer, the presence of hydrophobic dominions on the material surface, due to the interpenetrating polymerization of pHEMA with poly(caprolactone) (PCL), seems to ameliorate the cytocompatibility in terms of cell adhesion and metabolism. For our experiments, we used IMR-90 human fibroblasts, as these cells strongly regulate DNA, RNA, and protein synthesis as anchorage-dependent variables. Cell attachment on a pHEMA/PCL interpenetrating polymer network was optimal, suggesting a strong adhesion between the cells and the polymer surface. Cell adhesion was weaker on pHEMA, as a significant fraction of the fibroblasts revealed a lack of spreading, with most cells remaining spherical. Moreover, only fibroblasts seeded on pHEMA significantly decreased mRNA synthesis; collagen production and cell shapes ranged from fully flat and proliferating, to minimally spread and nonproliferating. Finally, DNA synthesis, as a measure of cell proliferation, was markedly inhibited in cells cultured on pHEMA but not on pHEMA/PCL. In conclusion, our results suggest that control of cell growth and metabolism by biomedical polymers is based on physicochemical mechanism(s) in which the hydrophilicity/hydrophobicity ratio of the material surfaces may play an important role.
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PMID:The differential effects of poly(2-hydroxyethyl methacrylate) and poly(2-hydroxyethyl methacrylate)/poly(caprolactone) polymers on cell proliferation and collagen synthesis by human lung fibroblasts. 908 2

Morphology and immunohistochemical features of the developmental process of the human intrahepatic biliary system (IBS) are reviewed. Human IBS arises from the ductal plate, a double-layered cylindrical structure located at the interface between portal mesenchyme and primitive hepatocytes. The ductal plate first appears from primitive hepatocytes (hepatoblasts) around 8 gestational weeks (GW), and its formation proceeds from the hepatic hilum to the periphery. The ductal plate gradually undergoes remodeling from 12 GW; some parts of the ductal plate disappear and other parts migrate into the portal mesenchyme. Around 20 GW, the migrated duct cells transform into immature bile ducts and peribiliary glands. Some immature peribiliary glands transform into pancreatic acinar cells around postnatal 3 months. The immature biliary elements express cytokeratins no. 7, 8, 18 and 19. Several growth factors (TGF-alpha, HGF) and their receptors (EGFR, MET, ERBB2) were expressed in the primitive IBS cells. Some extracellular matrix proteins including type IV collagen, laminin and tenascin are expressed in the mesenchyme around the primitive IBS. During IBS remodeling, apoptosis and cell proliferation occur with appropriate expression of apoptosis-related proteins (bcl-2, Fas, c-myc, Lewis(y)). Some pancreatic digestive enzymes (alpha-amylase, trypsinogen, lipase), cathepsin B, and matrix metalloproteinases (MMP-1, 2, 3, 9) and their inhibitors (TIMP-1, 2) are expressed in the remodeling IBS cells. Glycoconjugate residues of glycoproteins gradually appear during IBS development. The appropriate expression of these immunophenotypes may play an important role in the normal development of IBS.
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PMID:Normal and abnormal development of the human intrahepatic biliary system: a review. 914 36

Cleavage fragment length polymorphism analysis with silver staining visualization (CFLPA-SS) was used for the detection of mutations previously detected by single strand conformation (SSCA) or heteroduplex analyses (HA); in order to assess this new method for mutation screening. The analysed mutations include single nucleotide transitions, transversions, a deletion and a duplication in the following genes: CFTR (cystic fibrosis transmembrane conductance regulator), COL4A5 (collagen type 4 alpha 5 chain), PKD1 (polycystic kidney disease 1), and FGFR3 (fibroblast growth factor receptor 3). Peripheral blood leukocyte genomic DNA was isolated, amplified by polymerase chain reaction (PCR), and then cleaved by Cleavase I enzyme at different temperatures. Electrophoresis of the fragments on denaturing polyacrylamide gel was followed by silver staining for 1 min. All 13 mutations investigated were reproducibly detected. CFLPA-SS proved to be a reliable method for mutation detection and more rapid than SSCA and HA.
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PMID:Detection of mutations in human genes by a new rapid method: cleavage fragment length polymorphism analysis (CFLPA). 916 Mar 31

Our aim was to study the role of various extracellular matrices (ECM) on growth and differentiation of marrow stromal cells in vitro. Morphology changes, gene expression, and enzymatic activities were monitored in stromal osteoblastic MBA-15 and adipocytic 14F1.1 cells. These stromal cells were plated on dishes precoated with different substrata, such as matrigel (basement membrane), collagen type I, and endothelial ECM, and compared with cells plated on protein-free dishes. Striking morphological differences were observed when the cells grew on these different substrata. Changes in cell shape and growth also led to differential mRNA expression and enzymatic activities. When MBA-15 cells were plated on collagen, there was a decrease in mRNA for alkaline phosphatase (ALK-P), osteopontin (OP), and osteonectin (ON), and an increase in mRNA for procollagen (I). A differential effect was noted on 14F1.1 cells, the mRNA for ALK-P increased, the expressions of OP and ON lowered, and no expression for procollagen (I) was monitored. MBA-15 cells cultured on matrigel had decreased mRNA for ALK-P and OP, while they had increased ON mRNA expression and remained unchanged for procollagen I. No change in mRNA expression by 14F1.1 cells was monitored when cultured on matrigel. Functional enzymatic activities of ALK-P markedly decreased in MBA-15 cells cultured on various substrata, and increased or were unchanged in 14F1.1 cells. An additional enzyme, neutral endopeptidase (CD10/NEP), altered differentially in both cell types; this enzymatic activity increased or was unchanged when cells were cultured on these matrices. The results indicate a specific role for different ECM on various stromal cell types and their function.
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PMID:Phenotypic expression of marrow cells when grown on various substrata. 917 88

PD 089828, a novel protein tyrosine kinase inhibitor of a new structural class, the 6-aryl-pyrido-[2,3-d]pyrimidines, was identified by screening a compound library with assays that measured protein tyrosine kinase activity. PD 089828 was found to inhibit human full-length fibroblast growth factor (FGF) receptor-1 (FGFR-1), platelet-derived growth factor (PDGF) receptor beta subunit (PDGFR-beta), Src nonreceptor tyrosine kinase (c-Src) and epidermal growth factor (EGF) receptor (EGFR) tyrosine kinases with half-maximal inhibitory potencies (IC50 values) of 0.15 +/- 0.02 (n = 4), 0.18 +/- 0.04 (n = 3), 1.76 +/- 0.28 (n = 4) and 5.47 +/- 0.78 (n = 6) microM, respectively. PD 089828 was further characterized as an ATP competitive inhibitor of the growth factor receptor tyrosine kinases (FGFR-1, PDGFR-beta and EGFR) but a noncompetitive inhibitor of c-Src tyrosine kinase with respect to ATP. In addition, PD 089828 inhibited PDGF- and EGF-stimulated receptor autophosphorylation in vascular SMC (VSMC) and basic FGF-mediated tyrosine phosphorylation in A121 cells with IC50 values similar to the potencies observed for inhibition of receptor tyrosine kinase activity. The inhibition of PDGF receptor autophosphorylation in VSMC by PD 089828 occurred rapidly, with maximal effects reached within 5 min of drug exposure. Inhibition after single exposure was long lasting but also rapidly reversible, occurring within 5 min after drug removal. The PDGF-induced association of downstream signaling proteins, including phosphoinositide-3-kinase (PI-3K), growth factor receptor binding protein-2 (GRB2), SH-2 domain and collagen like (Shc) and phospholipase Cgamma (PLCgamma), with VSMC PDGF receptors was also blocked as a result of the inhibition of PDGF-stimulated receptor autophosphorylation by PD 089828. PD 089828 also inhibited the PDGF-induced tyrosine phosphorylation of the 44- and 42-kDa mitogen-activated protein kinase isoforms. Moreover, the effects of PD 089828 were demonstrated in functional assays in which PDGF-stimulated DNA synthesis, PDGF-directed migration and serum-stimulated growth of VSMC were all inhibited to the same extent as PDGF receptor autophosphorylation (IC50 = 0.8, 4.5 and 1.8 microM, respectively). These results highlight the biological characteristics of PD 089828 as a novel, broadly active protein tyrosine kinase inhibitor with long-lasting but reversible cellular effects. The potential therapeutic use of these broadly acting, nonselective inhibitors as antiproliferative and antimigratory agents could extend to such diseases as cancer, atherosclerosis and restenosis in which redundancies in growth-signaling pathways are known to exist.
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PMID:Inhibition of growth factor-mediated tyrosine phosphorylation in vascular smooth muscle by PD 089828, a new synthetic protein tyrosine kinase inhibitor. 919 Aug 82

The abilities of isolates of saprophytes (Neurospora crassa, Aspergillus nidulans), an opportunistic human pathogen (Aspergillus fumigatus), an opportunistic insect pathogen (Aspergillus flavus), plant pathogens (Verticillium albo-atrum, Verticillium dahliae, Nectria haematococca), a mushroom pathogen (Verticillium fungicola) and entomopathogens (Verticillium lecanii, Beauveria bassiana, Metarhizium anisopliae) to utilize plant cell walls and insect cuticle components in different nutrient media were compared. The pathogens showed enzymic adaptation to the polymers present in the integuments of their particular hosts. Thus, the plant pathogens produced high levels of enzymes capable of degrading pectic polysaccharides, cellulose and xylan, as well as cutinase substrate, but secreted little or no chitinase and showed no proteolytic activity against elastin and mucin. The entomopathogens and V. fungicola degraded a broad spectrum of proteins (including elastin and mucin) but, except for chitinase, cellulase (V. lecanii and V. fungicola only) and cutinase (B. bassiana only), produced very low levels of polysaccharidases. The saprophytes (Neu. crassa and A. nidulans) and the opportunistic pathogens (A. fumigatus and A. flavus) produced the broadest spectrum of protein and polysaccharide degrading enzymes, indicative of their less specialized nutritional status. V. lecanii and V. albo-atrum were compared in more detail to identity factors that distinguish plant and insect pathogens. V. albo-atrum, but not V. lecanii, grew well on different plant cell wall components. The major class of proteases produced in different media by isolates of V. albo-atrum and V. dahliae were broad spectrum basic (pI > 10) trypsins which degrade Z-AA-AA-Arg-NA substrates (Z, benzoyl; AA, various amino acids; Na, nitroanilide), hide protein azure and insect (Manduca sexta) cuticles. Analogous peptidases were produced by isolates of V. lecanii and V. fungicola but they were specific for Z-Phe-Val-Arg-NA. V. albo-atrum and V. dahliae also produced low levels of neutral (pI ca 7) and basic (pI ca 9.5) subtilisin-like proteases active against a chymotrypsin substrate (Succinyl-Ala2-Pro-Phe-NA) and insect cuticle. In contrast, subtilisins comprised the major protease component secreted by V. lecanii and V. fungicola. Both V. lecanii and V. albo-atrum produced the highest levels of subtilisin and trypsin-like activities during growth on collagen or insect cuticle. Results are discussed in terms of the adaptation of fungi to the requirements of their ecological niches.
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PMID:Adaptation of proteases and carbohydrates of saprophytic, phytopathogenic and entomopathogenic fungi to the requirements of their ecological niches. 920 74

Much attention has recently focused upon hepatocyte growth factor (HGF) as a potential regulator of epithelial branching morphogenesis. However, since neither the HGF nor c-met "knockout" mice show abnormal kidney branching morphogenesis, we sought to analyze the relative importance of HGF in in vitro branching morphogenesis compared with other factors secreted by the embryonic kidney. Exploiting an assay that employs kidney epithelial cells (murine inner medullary collecting duct, mIMCD3) seeded in collagen cocultured with the embryonic kidney, we found that a tyrosine kinase inhibitor that is highly specific for the epidermal growth factor (EGF) receptor (EGFR), tyrphostin AG1478, inhibited mIMCD3 cell process formation (an early step in branching tubulogenesis) by 40%, whereas high concentrations of neutralizing anti-HGF antibodies had a lesser effect (20% inhibition), suggesting that EGFR ligands account for a larger fraction of branching morphogens secreted by the embryonic kidney than HGF. In addition, when an embryonic epithelial cell line derived from c-met (-/-) mice was cocultured with the embryonic kidney, these c-met (-/-) cells underwent process formation. EGFR ligands but not HGF were able to induce branching tubulogenesis in these cells. All EGFR ligands tested, including EGF, transforming growth factor-alpha, heparin-binding EGF, betacellulin, and amphiregulin, induced mIMCD3 cell tubulogenesis. EGFR ligands caused upregulation of urokinase, urokinase receptor, and matrix metalloprotease-1, and tubulogenesis could be inhibited by the metalloprotease inhibitor 1,10-phenanthroline. Our results support the notion that multiple parallel and potentially redundant growth factor-dependent pathways regulate branching tubulogenesis.
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PMID:EGF receptor ligands are a large fraction of in vitro branching morphogens secreted by embryonic kidney. 932 21


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