Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies suggest that prostaglandin E may have the ability to suppress cytokine responsiveness. We examined the effects of prostaglandin E administration on several parameters of the acute and chronic hepatic injury induced by bile duct ligation. Enisoprost, a prostaglandin E(1) analog was found to suppress early hepatic and Ito cell type I collagen gene expression without diminishing the induction of the fibrogenic cytokine, transforming growth factor beta. Overall hepatic inflammation and cell proliferation were not altered, suggesting that prostaglandin E acts distal to the initial injurious event(s). During the later phases, drug administration reduced total collagen accumulation as well as type I collagen periductular infiltration associated with early nodule formation. Ito cell mitogenesis occurs during liver injury and fibrogenesis in vivo coincident with the de novo expression of Ito cell platelet-derived growth factor beta (PDGFbeta) receptor messenger RNA. PDGF-induced mitogenesis was studied in cultured rat hepatic Ito cells which resemble the myofibroblast associated with liver injury. Pretreatment with prostaglandin E markedly suppressed the PDGF response in a dose-dependent fashion. The PDGF-induced cascade was studied plus minus PGE to determine the level of regulation which induced the observed suppression. PGE caused no apparent diminution in the abundance of the surface PDGFbeta receptor nor its subsequent activation and tyrosine phosphorylation following PDGF stimulation. The cytoplasmic "secondary messengers" mitogen-activated protein kinase pp42--44 and raf kinase appeared to be comparably induced and therefore unaffected by PGE. Raf perinuclear translocation was also intact, and comparable degrees of nuclear egr, fos, and jun expression occurred. Because other studies have suggested that many of these features of the PDGF cascade may be causally and sequentially linked, the data collectively suggest that the dominant PGE mitogenic suppressive effect resides at a Raf-MAP parallel pathway or at a nuclear level distal to the induction of these early growth response genes.
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PMID:Prostaglandin E Suppresses Hepatic Fibrosis: Section I. The In Vivo Approach; Section II. The In Vitro Approach. 1185 47

Non-aromatizable androgens have significant beneficial effects on skeletal homeostasis independently of conversion to estradiol, but the effects of androgens on bone cell metabolism and cell proliferation are still poorly understood. Using an osteoblastic model with enhanced androgen responsiveness, MC3T3-E1 cells stably transfected with androgen receptor (AR) under the control of the type I collagen promoter (colAR-MC3T3), the effects of androgens on mitogenic signaling were characterized. Cultures were treated with the non-aromatizable androgen 5alpha-dihydrotestosterone (DHT) and the effects on osteoblast viability were determined as measured by an MTT assay. A complex response was observed in that continuous short-term DHT treatment enhanced osteoblast viability, but with longer-term DHT treatment inhibition was observed. The inhibition by DHT was prevented by the specific AR antagonist hydroxyflutamide, and was also observed in primary cultures of normal rat calvarial osteoblasts. In order to identify potential mediators of this effect, mitogenic pathway-specific cDNA microarrays were interrogated. Reduced hybridization of several genes important in MAP kinase-mediated signaling was observed, with the most dramatic effect on Elk-1 expression. Analysis of phosphorylation cascades demonstrated that DHT treatment inhibited phosphoERK1/2 levels, MAP kinase activation of Elk-1, Elk-1 protein and phosphoElk-1 levels, and downstream AP-1/luciferase reporter activity. Together, these data provide the first evidence that androgen inhibition of the MAP kinase signaling pathway is a potential mediator of osteoblast growth, and are consistent with the hypothesis that the MAP cascade may be a specific downstream target of DHT.
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PMID:Androgen inhibition of MAP kinase pathway and Elk-1 activation in proliferating osteoblasts. 1476 3

During endochondral ossification, type I collagen is synthesized by osteoblasts together with some hypertrophic chondrocytes. Type I collagen has also been reported to be progressively synthesized in degenerative joints. Because Matrix Metalloproteinase-13 (MMP-13) plays an active role in remodeling cartilage in fetal development and osteoarthritic cartilage, we investigated whether type I collagen could activate MMP-13 expression in chondrocytes. We used a well-established chondrocytic cell line (MC615) and we found that MMP-13 expression was induced in MC615 cells cultured in type I collagen gel. We also found that alpha1beta1 integrin, a major collagen receptor, was expressed by MC615 cells and we further assessed the role of alpha1beta1 integrin in conducting MMP-13 expression. Induction of MMP-13 expression by collagen was potently and synergistically inhibited by blocking antibodies against alpha1 and beta1 integrin subunits, indicating that alpha1beta1 integrin mediates the MMP-13-inducing cellular signal generated by three-dimensional type I collagen. We also determined that activities of tyrosine kinase and ERK and JNK MAP kinases were required for this collagen-induced MMP-13 expression. Interestingly, bone morphogenetic protein (BMP)-2 opposed this induction, an effect that may be related to a role of BMP-2 in the maintenance of cartilage matrix.
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PMID:Integrin alpha1beta1 mediates collagen induction of MMP-13 expression in MC615 chondrocytes. 1619 11

Tendon injuries cause considerable morbidity in the general adult population. The tenocytes within the tendon have the full capacity to heal the tendon intrinsically. Activated protein C (APC) plays an important role in coagulation and inflammation and more recently has been shown to promote cutaneous wound healing. In this study we examined whether APC can induce a wound healing phenotype in tenocytes. Sheep tenocytes were treated with APC, endothelial protein C receptor (EPCR) blocking antibody (RCR252) and/or EPCR small interfering (si)RNA. Cell proliferation and migration were measured by crystal violet assay and a scratch wounding assay, respectively. The expression of EPCR, matrix metalloproteinase (MMP)-2, type I collagen and MAP kinase activity were detected by real time PCR, zymography, immunofluorescence, immunohistochemistry and Western blotting. APC stimulated proliferation, MMP-2 activity and type I collagen deposition in a dose-dependent manner and promoted migration of cultured tenocytes. APC dose-dependently stimulated phosphorylated (P)-ERK2 and inhibited P-p38. Interestingly, tenocytes expressed EPCR protein, which was up-regulated by APC. When tenocytes were pre-treated with RCR252 or EPCR siRNA the effect of APC on proliferation, MMP-2 and type 1 collagen synthesis and MAP kinases was blocked. APC promotes the growth, MMP-2 activity, type I collagen deposition and migration of tenocytes. Furthermore, EPCR is expressed by tenocytes and mediates the actions of APC, at least partly by signalling through selective MAP kinases. These data implicate APC as a potential healing agent for injured tendons.
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PMID:Activated protein C mediates a healing phenotype in cultured tenocytes. 1846 56

Collagen is responsible for maintenance of connective tissue integrity, and through interaction with integrin receptors may participate in regulation of numerous physiological and pathological processes. An important role in collagen biosynthesis plays prolidase. It was previously found that nickel chloride inhibited prolidase activity in Chinese hamster ovary cells (CHO-C9). The cells lack any detectable ornithine aminotransferase and P5C synthase activities, and therefore require addition of free proline or glicyl-proline (converted to glycine and proline) for growth. We have found that Ni(II) contributed to decrease in collagen and hydroxyproline content in CHO cells incubated with Gly-Pro, whereas it had no effect on hydroxyproline content in the cells incubated with proline. Decrease in collagen content was not related to decrease in type I collagen mRNA level suggesting regulation of this process at post-transcriptional level. However decrease in expression of Sos and phosphorylated MAP-kinases were found in the cells growing in the presence of Gly-Pro and Ni(II). Decrease in the expression of these proteins was not related to inhibition of signalling induced by growth factors, since no changes were observed in expression of AKT in CHO cells incubated with Ni(II). The results presented provide evidence for important role of prolidase in collagen biosynthesis.
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PMID:Prolidase dependent inhibition of collagen biosynthesis in Chinese hamster ovary cells. 1855 Jun 32

We examined the hypothesis that human mesenchymal stem cells detect physiological mechanical signals. Human bone marrow stromal cells (HBMSCs) were exposed to fluid shear stress of 12 dynes/cm(2) and analysed for their ability to express osteoblast-specific markers and associated signalling pathways. HBMSCs showed a significant increase in alkaline phosphatase (ALP) gene expression and a marked decrease in type I collagen, while no effect on Cbfa1/Runx2 was detected. This regulation is related to p38 and ERK1/2 activation, although the use of specific inhibitors to these two MAP kinases suggests that ALP mRNA induction is especially dependent on p38 activity, while type I collagen downregulation is ERK1/2-dependent. Interestingly, the expression of connexin43, which is involved in cell-to-cell communication of osteoblastic cells through gap junction formation, and its distribution through the cells, were modified by fluid flow (FF). HBMSCs are sensitive to shear stress and it appears essential to take their responsiveness into consideration before associating these regenerative cells with a bioactive biomaterial in a new bone tissue-engineering strategy.
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PMID:Responsiveness of human bone marrow stromal cells to shear stress. 1928 26

During the later stages of lung development, two types of pneumocytes, cuboidal type II (AECII) and flattened type I (AECI) alveolar epithelial cells, form distal lung saccules. Here, we highlight how fibroblasts expressing MAP-microtubule affinity regulating kinase 1 (Mark1) are required for the terminal stages of pulmonary development, called lung sacculation. In Mark1-knockout (KO) mice, distal sacculation and AECI flattening are significantly impaired. Fetal epithelial cells generate alveolar organoids and differentiate into pneumocytes when co-cultured with fibroblasts. However, the size of organoids decreased and AECI flattening was impaired in the presence of Mark1 KO fibroblasts. In Mark1 KO fibroblasts themselves, cilia formation and the Hedgehog pathway were suppressed, resulting in the loss of type I collagen expression. The addition of type I collagen restored AECI flattening in organoids co-cultured with Mark1 KO fibroblasts and rescued the decreased size of organoids. Mathematical modeling of distal lung sacculation supports the view that AECI flattening is necessary for the proper formation of saccule-like structures. These results suggest that Mark1-mediated fibroblast activation induces AECI flattening and thereby regulates distal lung sacculation.
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PMID:Mark1 regulates distal airspace expansion through type I pneumocyte flattening in lung development. 3171 61