Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammatory bowel disease is incurable and relapsing disease. In order to clarify the effect of HGF gene therapy for inflammatory bowel disease, the adenoviral-mediated HGF gene was intrarectally administered into TNBS-colitis-induced Balb/c mice. Adenoviral-mediated gene delivery targetted its expression mainly to intestinal epithelial cells. Mucosal damage of HGF-treated intestine was significantly improved, and compared with LacZ-treated and saline administered mice (P<0.05, each). The mice treated with intrarectal administration of pAxCAHGF showed an increased average of body weight in comparison with that of pAxCALacZ-treated and saline-treated mice (P<0.05, each). The PCNA-positive cells in pAxCALacZ-treated mice were 44.7+/-4.9%, 51.7+/-6.6%, and 53.9+/-4.5% at 10, 15, and 21 days after TNBS administration, however those in pAxCAHGF-treated mice were increased to 74.3+/-5.1%, 67.1+/-2.6%, and 69.2+/-4.6% (P<0.05, each). The TUNEL-positive cells in pAxCALacZ-treated mice were 13.3+/-5.2%, 11.5+/-2.1%, and 7.2+/-5.2%, respectively. However, those in pAxCAHGF-treated mice at 10, 15, and 21 days were significantly decreased to 5.4+/-1.8%, 3.8+/-1.3%, and 5.7+/-2.8% (P<0.05, respectively). Expression of ERK1/2 was stronger in pAxCAHGF mice than in pAxCALacZ. These data suggest that adenoviral-mediated HGF gene therapy via an intrarectal route is a promising therapy for inflammatory bowel disease.
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PMID:Therapeutic effect of adenoviral-mediated hepatocyte growth factor gene administration on TNBS-induced colitis in mice. 1576 56

It has been shown that in hereditary and most sporadic colon tumours, components of the Wnt pathway are mutated. The Wnt target MET has been implicated in the development of colon cancer. Here, we show that overexpression of wild-type or a constitutively activated form of MET in colon epithelial cells leads to increased transformation irrespective of Wnt signalling. Fetal human colon epithelial cells without aberrant Wnt signalling were transfected with wild-type or mutated MET constructs. Expression of these constructs leads to increased phosphorylation of MET and its downstream targets PKB and MAPK. Upon stimulation with HGF, the expression of E-cadherin is downregulated in wild-type MET-transfected cells, whereas cells expressing mutated MET show low E-cadherin levels independent of stimulation with ligand. This implies a higher migratory propensity of these cells. Furthermore, fetal human colon epithelial cells expressing the mutated form of MET have colony-forming capacity in soft agar, while cells expressing wild-type MET show an intermediate phenotype. Subcutaneous injection of mutated MET-transfected cells in nude mice leads to the formation of tumours within 12 days in all mice injected. At this time point, mock-transfected cells do not form tumours, while wild-type MET-transfected cells form subcutaneous tumours in one out of five mice. We thus show that MET signalling can lead to increased transformation of colon epithelial cells independent of Wnt signalling and in this way could play an essential role in the onset and progression of colorectal cancer.
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PMID:MET signalling in primary colon epithelial cells leads to increased transformation irrespective of aberrant Wnt signalling. 1578 35

Human retinal pigmented epithelial cell (hRPE) proliferation plays a significant role in various proliferative diseases associated to the retina that leads to loss of vision, such as proliferative vitreoretinopathy. In the current study, the role of the bovine vitreous lipid factor (bVLF) in hRPE cell proliferation has been investigated. bVLF is a bioactive lipid isolated from the bovine vitreous body with strong Ca(2+)-mobilizing activity in fibroblast. In the first approach, the effects of bVLF on Ca(2+)-mobilizing activity were investigated in hRPE. The results showed that bVLF induced, in a dose-dependent manner, a Ca(2+) mobilization from PA-sensitive intracellular stores [non-Ins(1,4,5)P(3)-sensitive stores], in which extracellular Ca(2+) participated. The increase in intracellular Ca(2+) was associated with a dose-dependent inhibiting effect on cell proliferation. At a dose of 10 microg/mL, bVLF caused a 26% or a 44% inhibition in hRPE cell proliferation during the 3- or the 6-day culture periods, respectively. These effects appear to be specific in hRPE cells, since EFGR-T17 fibroblast cells treated with equivalent amounts of bVLF did not show any inhibiting effects. This inhibitory action was not associated to apoptotic/necrotic processes. Furthermore, bVLF inhibited EGF-, bFGF-, IGF-I-, PDGF-, HGF- and VEGF-induced proliferation of the hRPE cells. Moreover, this inhibitory response was also observed in FBS-induced hRPE cell proliferation. bVLF, at a concentration of 10 microg/mL, induced 16% inhibition of proliferation during a culture period of 3 days. This inhibitory action was greater during the 6-day culture period, exceeding 40%. With regard to this action, the results showed that bVLF has a potent inhibitory effect on ERK1/2 activation, and plays a key role in the control of hRPE cell proliferation. These observations contribute to the knowledge of inhibitory factors responsible for keeping antiproliferative environment that preserve the RPE-associated activities in normal states. It advances the interesting possibility that this factor or a factor with characteristics common to bVLF might be involved in the pathogenesis of abnormal proliferative eye processes.
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PMID:The bovine vitreous-derived lipid factor (bVLF) is a powerful inhibitor of retinal pigmented epithelial (hRPE) cell proliferation. 1600 88

The expression of syndecan-1 generally appears down-regulated in human cancers and experimental models, whereas transfectional expression of syndecan-1 in cancer cells has been shown to inhibit aspects of their malignant behavior. To clarify how reduced levels of syndecan-1 may confer enhanced invasiveness, we transfected human ovarian cancer cell line HRA with antisense (AS) syndecan-1 oligodeoxynucleotide (ODN) and compared the properties of transfected cells to those of parental cells or sense (S) syndecan-1 cells. Here, we show: 1) there was lower proliferation in the AS syndecan-1 cells compared to controls (parental HRA cells and S syndecan-1 cells) when cells were incubated with HB-GFs (HB-EGF, HGF, or FGF2); 2) transfection of HRA cells with a syndecan-1 AS ODN enhanced the increase in HB-GF-dependent invasiveness; 3) in contrast, IGF-I stimulated cell proliferation and invasion, irrespective of whether cells were transfected with the AS syndecan-1 gene; 4) IGF-I stimulated ERK1/2 activation and uPA expression in both the control and AS cells, whereas the net effect of the reduction of syndecan-1 is to shift the HB-GF dose-response curve to the right; 5) the AS cells reduced activation and up-regulation of ERK1/2 phosphorylation and uPA expression, respectively, in response to HB-GFs; and 6) in comparison with early stage ovarian cancer tissues, there was a 3-fold decrease in syndecan-1 mRNA levels in advanced stage tissues. Taken together, these data suggest that decreased syndecan-1 expression may be associated with enhanced cell invasion possibly through the uPA-independent mechanism.
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PMID:Reduced syndecan-1 expression stimulates heparin-binding growth factor-mediated invasion in ovarian cancer cells in a urokinase-independent mechanism. 1601 29

Invasive and proliferative phenotypes are fundamental components of malignant disease, yet basic questions persist about whether tumor cells can express both phenotypes simultaneously and, if so, what are their properties. Suitable in vitro models that allow characterization of cells that are purely invasive are limited because proliferation is required for cell maintenance. Here, we describe glioblastoma cells that are highly invasive in response to hepatocyte growth factor/scatter factor (HGF/SF). From this cell population, we selected subclones that were highly proliferative or displayed both invasive and proliferative phenotypes. The biological activities of invasion, migration, urokinase-type plasminogen activation, and branching morphogenesis exclusively partitioned with the highly invasive cells, whereas the highly proliferative subcloned cells uniquely displayed anchorage independent growth in soft agar and were highly tumorigenic as xenografts in immune-compromised mice. In response to HGF/SF, the highly invasive cells signal through the MAPK pathway, whereas the selection of the highly proliferative cells coselected for signaling through Myc. Moreover, in subcloned cells displaying both invasive and proliferative phenotypes, both signaling pathways are activated by HGF/SF. These results show how the mitogen-activated protein kinase and Myc pathways can cooperate to confer both invasive and proliferative phenotypes on tumor cells and provide a system for studying how transitions between invasion and proliferation can contribute to malignant progression.
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PMID:Proliferation and invasion: plasticity in tumor cells. 1602 25

We previously showed that the Kaposi Sarcoma line KS-IMM express a functional Met tyrosine kinase receptor, which, upon HGF stimulation, activates motogenic, proliferative, and invasive responses. In this study, we investigated the signalling pathways activated by HGF, as well as by Met monoclonal antibodies (Mabs), acting as full or partial agonists. The full agonist Mab mimics HGF in all biological and biochemical aspects. It elicits the whole spectrum of responses, while the partial agonist Mab induces only wound healing. These differences correlated with a more prolonged and sustained tyrosine phosphorylation of the receptor and MAPK evoked by HGF and by the full agonist Mab, relative to the partial agonist Mab. Since Gab1, JNK and PI 3-kinase are activated with same intensity and kinetics by HGF and by the two agonist antibodies, it is concluded that level and duration of MAPK activation by Met receptor are crucial for the induction of a full HGF-dependent mitogenic and invasive program in KS cells.
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PMID:Agonist Met antibodies define the signalling threshold required for a full mitogenic and invasive program of Kaposi's Sarcoma cells. 1603 97

During the first trimester of pregnancy, well-differentiated primary cells of the placenta known as trophoblast cells grow in an invasive and destructive fashion similar to malignancies, but limited in space and time. The comparison of trophoblast cells with their malignant counterpart, human choriocarcinoma cells, offers an attractive model to understand the origin or development of malignant growth. Several cytokines and growth factors are known to influence trophoblast migration (e.g. EGF, IGF-2, HGF), proliferation (e.g. leptin, HGF, GM-CSF) and/or invasion (e.g. leukemia inhibitory factor, LIF), each factor utilizing at least one pathway for intracellular signaling in the trophoblast. Two pathways that are crossed especially often mediate the signals of these factors and are simultaneously well established in terms of tumor invasion: the Janus kinase-signal transducers and activators of transcription (Jak-Stat) and receptor-associated tyrosine kinase-mitogen-activated protein kinase (RTK-MAPK) pathways. These two pathways are detrimental for reproduction in general, and in part for placenta development, as a series of knockout experiments demonstrate. Aspects of each pathway are also implicated to be involved in trophoblast invasion, e.g. STAT3 is constitutively activated in invasive first trimester trophoblast cells, and activated ERK is detectable in intermediate trophoblast cells, an invasive phenotype. Interaction at several intersection points between the pathways has been described in several cell systems so that the same would seem to be possible in trophoblast cells. In this review, some of the possible areas of interaction are alluded to.
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PMID:Signal transduction in trophoblast invasion. 1612 46

This paper reviews cellular and molecular mechanisms of gastrointestinal ulcer healing. Ulcer healing, a genetically programmed repair process, includes inflammation, cell proliferation, re-epithelialization, formation of granulation tissue, angiogenesis, interactions between various cells and the matrix and tissue remodeling, all resulting in scar formation. All these events are controlled by the cytokines and growth factors (EGF, PDGF, KGF, HGF, TGFbeta, VEGF, angiopoietins) and transcription factors activated by tissue injury in spatially and temporally coordinated manner. These growth factors trigger mitogenic, motogenic and survival pathways utilizing Ras, MAPK, PI-3K/Akt, PLC-gamma and Rho/Rac/actin signaling. Hypoxia activates pro-angiogenic genes (e.g., VEGF, angiopoietins) via HIF, while serum response factor (SRF) is critical for VEGF-induced angiogenesis, re-epithelialization and muscle restoration. EGF, its receptor, HGF and Cox2 are important for epithelial cell proliferation, migration re-epithelializaton and reconstruction of gastric glands. VEGF, angiopoietins, nitric oxide, endothelin and metalloproteinases are important for angiogenesis, vascular remodeling and mucosal regeneration within ulcer scar. Circulating progenitor cells are also important for ulcer healing. Local gene therapy with VEGF + Ang1 and/or SRF cDNAs dramatically accelerates esophageal and gastric ulcer healing and improves quality of mucosal restoration within ulcer scar. Future directions to accelerate and improve healing include the use of stem cells and tissue engineering.
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PMID:Cellular and molecular mechanisms of gastrointestinal ulcer healing. 1618 17

Embryonal central nervous system (CNS) tumors, which comprise medulloblastoma, are the most common malignant brain tumors in children. The role of the growth factor scatter factor/hepatocyte growth factor (SF/HGF) and its tyrosine kinase receptor c-Met in these tumors has been until now completely unknown. In the present study, we show that human embryonal CNS tumor cell lines and surgical tumor specimens express SF/HGF and c-Met. Furthermore, c-Met mRNA expression levels statistically significantly correlate with poor clinical outcome. Treatment of medulloblastoma cells with SF/HGF activates c-Met and downstream signal transduction as evidenced by c-Met, mitogen-activated protein kinase, and Akt phosphorylation. SF/HGF induces tumor cell proliferation, anchorage-independent growth, and cell cycle progression beyond the G1-S checkpoint. Using dominant-negative Cdk2 and a degradation stable p27 mutant, we show that cell cycle progression induced by SF/HGF requires Cdk2 function and p27 inhibition. SF/HGF also protects medulloblastoma cells against apoptosis induced by chemotherapy. This cytoprotective effect is associated with reduction of proapoptotic cleaved poly(ADP-ribose) polymerase and cleaved caspase-3 proteins and requires phosphoinositide 3-kinase activity. SF/HGF gene transfer to medulloblastoma cells strongly enhances the in vivo growth of s.c. and intracranial tumor xenografts. SF/HGF-overexpressing medulloblastoma xenografts exhibit increased invasion and morphologic changes that resemble human large cell anaplastic medulloblastoma. This first characterization establishes SF/HGF:c-Met as a new pathway of malignancy with multifunctional effects in human embryonal CNS tumors.
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PMID:The scatter factor/hepatocyte growth factor: c-met pathway in human embryonal central nervous system tumor malignancy. 1623 Mar 98

The aim of this study was to test the possibility of using human antibodies to study the pathogenic mechanism of SV40 and asbestos in a hamster mesothelioma model. The cellular lysates from human and hamster primary mesothelial cells were tested by Western blot analysis. All of the antibodies we tested (HGF, Notch, VEGF, Sp1, p53, PP2A, p-ERK1, p-c-jun, Fra1, Fra2, MMP1, MMP9, NFkappaB p65, IkappaB, GAPDH) cross-reacted with their hamster counterparts. These data indicate that hamster mesothelioma model and more in general hamster experimental model, can be used for functional studies because many mouse, rabbit, and goat monoclonal antibodies prepared against human antigens cross-react with their hamster counterparts.
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PMID:Cross reactivity between many anti-human antibodies for their hamster homologs provide the tools to study the signal transduction pathway activated by asbestos and SV40 in the malignant mesothelioma model. 1664 49


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