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)

The early events leading to the establishment of left ventricular hypertrophy associated to pressure overload (PO) are not well characterized. To explore these early events, aortic banding (AB) was performed in rats to induce left ventricle (LV) PO. Animals were sacrificed after 24, 48 h or 14 days. An echocardiogram was performed before the procedure and at sacrifice. LVs were preserved for the evaluation of fibrosis, angiotensin II (AT) receptors expression and stress-related MAP kinases (ERK 1/2, JNK and p38) pathways. We observed that concentric LV hypertrophy was established after only 14 days. Collagen I and fibronectin gene expressions were decreased the first 2 days after AB induction whereas AT receptors mRNA levels were sharply increased. ERK 1/2 and JNK activities in LV homogenates were decreased 24 h after AB but came back to normal after 14 days. p38 activity however was stable during the period studied. We also evaluated the presence of two phosphorylated transcription factors related to JNK signaling pathway (ATF-2 and c-Jun) in cardiomyocyte nuclei. The proportion of LV cell nuclei positive for these two activated transcription factors was significantly reduced in AB rats compared to sham. These results suggest that the early response of the LV to acute PO is to attenuate the expression of some pro-fibrotic and pro-hypertrophic signaling pathways and possibly AT signaling by decreasing ERK 1/2 and JNK relative activities.
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PMID:Early responses of the left ventricle to pressure overload in Wistar rats. 1815 33

This study explores the neuroprotective action of tumor necrosis factor-alpha (TNF-alpha) induced during physical exercise, which, consequently, reduces matrix metalloproteinase-9 (MMP-9) activity and ameliorates blood-brain barrier (BBB) dysfunction in association with extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation. Adult male Sprague-Dawley rats were subjected to exercise on a treadmill for 3 weeks. A 2-h middle cerebral artery occlusion and reperfusion was administered to exercised and nonexercised animals to induce stroke. Exercised ischemic rats were subjected to TNF-alpha inhibition and ERK1/2 by TNF-alpha antibody or UO126. Nissl staining of coronal sections revealed the infarct volume. Evans blue extravasation and water content evaluated BBB function. Western blot was performed to analyze protein expression of TNF-alpha, ERK1/2, phosphorylated ERK1/2, the basal laminar protein collagen IV, and MMP-9. The activity of MMP-9 was determined by gelatin zymography. Tumor necrosis factor-alpha expression and ERK1/2 phosphorylation were upregulated during exercise. Infarct volume, brain edema, and Evans blue extravasation all significantly decreased in exercised ischemic rats. Collagen IV production increased in exercised rats and remained high after stroke, whereas MMP-9 protein level and activity decreased. These results were negated and returned toward nonexercised values once TNF-alpha or ERK1/2 was blocked. We concluded that preischemic, exercise-induced TNF-alpha markedly decreases BBB dysfunction by using the ERK1/2 pathway.
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PMID:Preischemic induction of TNF-alpha by physical exercise reduces blood-brain barrier dysfunction in stroke. 1841 98

Collagen deposition is observed in a diverse set of pulmonary diseases, and the unraveling of the molecular signaling pathways that facilitate collagen deposition represents an ongoing area of investigation. The stress-activated protein kinase, c-Jun N-terminal kinase 1 (JNK1), is activated by a large variety of cellular stresses and environmental insults. Recent work from our laboratory demonstrated the critical role of JNK1 in epithelial to mesenchymal transition. The goal of the present study was to examine the involvement of JNK1 in subepithelial collagen deposition in mice subjected to models of allergic airways disease and interstitial pulmonary fibrosis. Activation of JNK was slightly enhanced in lungs from mice subjected to sensitization and challenge with ovalbumin (Ova), and predominant localization of phospho-JNK was observed in the bronchial epithelium. While mice lacking JNK1 (JNK1-/- mice) displayed enhanced lung inflammation and cytokine production compared with wild-type (WT) mice, JNK1-/- mice accumulated less subepithelial collagen deposition in response to antigen, and showed decreased expression of profibrotic genes compared with WT animals. Furthermore, transforming growth factor (TGF)-beta1 content in the bronchoalveolar lavage was diminished in JNK1-/- mice compared with WT animals subjected to antigen. Finally, we demonstrated that mice lacking JNK1 were protected against TGF-beta1 and bleomycin-induced pro-fibrotic gene expression and pulmonary fibrosis. Collectively, these findings demonstrate an important requirement for JNK1 in promoting collagen deposition in multiple models of fibrosis.
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PMID:c-Jun N-terminal kinase 1 is required for the development of pulmonary fibrosis. 1883 36

Metalloproteinase MT1-MMP is induced and Pro-MMP-2 up modulated early in rat preosteoblasts (ROB) set to differentiate. We here show that the induction of MMPs, accompanied by activation of Pro-MMP-2, occurs by 6 h of adhesion on endogenous extracellular matrix (ECM), Fibronectin (FN) and Collagen type I (CI). These events do not occur after adhesion on Collagen III (CIII), Vitronectin (VN) or BSA. Within the first hour on inducing substrata or plastic, FAK is unchanged and ERK(1,2), is activated, but this activation is not sufficient for MT1-MMP induction. The function of p38 MAPK and PTKs is not required for the induction by substrata of MMPs. Six hours after plating preosteoblasts on MMP-inducing substrata, complexes of beta1 integrin with MT1-MMP are formed, that contain integrin dimers specifically engaged by the substratum, alpha4 and alpha5 chains for cells plated on FN, and alpha2 chain for cells plated on CI and ECM. Induction of MT1-MMP and its expression during osteogenesis pleiotropically regulate alkaline phosphatase (AP) expression. During differentiation, variant clones derived from preosteoblasts and MMPs-over-expressing osteoblasts show high MT1-MMP level associated with high AP level both persisting in time, while inhibition of MMPs is accompanied by inhibition of AP. Up or down modulation of AP, transcriptionally or by inhibition of the enzyme activity, has no effect on level or timing of expression of MT1-MMP and Pro-MMP-2. The persistence in expression of MT1-MMP during differentiation, and the associated persistence in expression of AP, as well as their inhibition, both impair the formation of nodules and mineral deposition. A transient pattern of expression of MT1-MMP is required for the establishment of nodules, and MT1-MMP decrease is permissive for nodule mineralization. The expression of AP is required for nodule formation and its level modulates the mineralization. MT1-MMP has multiple functions and is implicated in multiple steps of the differentiation process, acting to regulate homeostasis of the osteogenic differentiation.
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PMID:Role of MT1-MMP in the osteogenic differentiation. 1902 88

Collagen XVII (COL17) participates in keratinocyte adhesion and possibly migration, as COL17 defects disrupt keratinocyte-basal lamina adhesion and underlie the disease non-Herlitz junctional epidermolysis bullosa. Using small interference RNA (siRNA) to knock down COL17 expression in HaCaT cells, we assessed cell characteristics, including adhesion, migration, and signaling. Control and siRNA-transfected keratinocytes showed no difference in adhesion on plastic dishes after incubation for 8 hours in serum-free keratinocyte-growth medium; however, when grown on collagen IV alone or BD matrigel (containing collagen IV and laminin isoforms), COL17-deficient cells showed significantly reduced adhesion compared with controls (P<0.01), and mitogen-activated protein kinase (MAPK)/ERK kinase (MEK)1/2 and MAPK showed reduced phosphorylation. Furthermore, COL17-deficient HaCaT cells plated on plastic exhibited reduced motility that was p38MAPK-dependent (after addition of the p38MAPK inhibitor SB203580). Together, these results suggest that COL17 has significantly wider signaling roles than were previously thought, including the involvement of COL17 in keratinocyte adhesion to collagen IV, in p38MAPK-dependent cell migration, and multiple cell signaling events pertaining to MEK1/2 phosphorylation.
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PMID:Collagen XVII participates in keratinocyte adhesion to collagen IV, and in p38MAPK-dependent migration and cell signaling. 1924 20

Understanding the mechanisms that regulate mechanosensitivity in osteoblasts is important for controlling bone homeostasis and the development of new drugs to combat bone loss. It is believed that prestress or force generation (the tensile stress within the cell body) plays an important role in regulating cellular mechanosensitivity. In the present study, a three-dimensional (3D) collagen culture was used to monitor the change in prestress of the osteoblast-like cells. Collagen hydrogel compaction has been used as an indicator of the change in the degree of cell prestress. Previous results in this model demonstrated that extracellular ATP reduced the mechanosensitivity of osteoblasts by reducing cellular prestress. To elucidate the potential mechanisms involved in this process, the signaling pathways downstream of P2 purinoceptors involved in regulating the compaction of type I collagen gels were investigated. By using specific inhibitors to these signaling pathways, we found that ATP-induced reduction in collagen gel compaction rate is dependent on mitogen-activated protein kinase (MAKP) and NF-kappaB pathways. However, blocking protein kinase C with GF109203X did not change the compaction kinetics in the presence of ATPgammaS. Moreover, blocking cyclic AMP (cAMP), phosphatidylinositol-3 kinase (PI3K), calmodulin (CaM) or L-type voltage sensitive calcium channels did not affect ATP's ability to reduce collagen gel compaction. The results from the present and previous studies indicate that extracellular ATP may act as a negative feedback modulator in the mechanotransduction system since mechanical stimuli increase ATP release from stimulated cells.
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PMID:Modulation of collagen gel compaction by extracellular ATP is MAPK and NF-kappaB pathways dependent. 1924 6

Collagen as a ligand for integrin receptors plays important role in the integrin - dependent regulation of cellular metabolism. Since betulinic acid (BA) evokes anticancer activity, its effect on collagen biosynthesis was studied in cultured endometrial adenocarcinoma cells. Confluent cells were treated with different concentrations of BA for 24 hours. It was found that BA inhibit collagen biosynthesis ([3H] proline incorporation assay). The mechanism of this phenomenon was found at the level of insulin-like growth factor-I receptor (IGF-IR) and alpha2 integrin signalling (Western immunoblot analysis). The expressions of IGF-I receptor and alpha2 integrin subunit as well as integrin activated focal adhesion kinase (FAK) were decreased in the cells treated with BA. It was accompanied by a parallel decrease in the expression of Sos protein and phosphorylated MAP-kinases (ERK1, ERK2) and up - regulation of NF-kappaB. The data suggest that BA-dependent inhibition of collagen biosynthesis in cultured human endometrial adenocarcinoma cells undergoes through alpha2 integrin and IGF-IR signaling that activate NF-kappaB, potent inhibitor of collagen gene expression.
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PMID:Mechanism of betulinic acid inhibition of collagen biosynthesis in human endometrial adenocarcinoma cells. 1946 59

Collagen-induced platelet activation is a complex process involving multiple signaling pathways. The role(s) of MAP kinases (ERKs and p38(MAPK)) are unclear, although at high, but not low, collagen concentrations p38(MAPK) is involved in cPLA(2)-mediated arachidonic acid release, prior to thromboxane generation. Cyclic nucleotides are conventionally regarded as mediators of platelet inhibition. However recent studies suggested a role for cGMP early in a MAP kinase pathway in platelet activation. In the current study the roles and relationships of MAP kinases, cyclic nucleotides and cPLA(2) in platelet activation by low-dose collagen and a thromboxane analogue (U46619) have been evaluated. Stimulants of neither adenylate cyclase (PGI(2)) nor guanylate cyclase (NaNP) alone had any effect on the basal phosphorylation of either MAP kinase. PGI(2) inhibited ERK/p38(MAPK) phosphorylation in response to both agonists which was unaffected by a cPLA(2) inhibitor (AACOCF(3)). NaNP inhibited collagen-induced ERK/p38(MAPK) phosphorylation, which was enhanced by AACOCF(3) and reversed by a guanylate cyclase inhibitor (ODQ). However NaNP had no effect on U46619-induced p38(MAPK) phosphorylation. Thus adenylate cyclase activation inhibits low-dose collagen-induced MAP kinase phosphorylation both prior, and distal, to thromboxane release. The study also supports an inhibitory, rather than stimulatory, role for guanylate cyclase in platelet signaling.
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PMID:Cyclic nucleotides inhibit MAP kinase activity in low-dose collagen-stimulated platelets. 1959 42

This study tested the hypothesis that mitogen-activated protein kinase inhibitors suppress hypertrophy and enhance chondrogenesis during chondrogenesis of multipotent mesenchymal stromal cells (MSCs). The effects of PD98059 (an extracellular signal-regulated kinase-1/2 inhibitor) and SB203580 (a p38 inhibitor) were tested on bone marrow-derived MSCs (BMMSCs) and adipose tissue-derived MSCs (ATMSCs). In vitro pellet cultures were carried out using 2.5 x 10(5) MSCs in a chondrogenic medium containing 5 ng/mL of transforming growth factor-beta(2) (TGF-beta(2)) for BMMSCs, and 5 ng/mL of TGF-beta(2) and 100 ng/mL of bone morphogenetic protein-7 (BMP-7) for ATMSCs. From the 14th day of culture, the pellets were additionally treated with PD98059 or SB203580. After 14 more days of in vitro culture, pellets were harvested for analysis. PD98059 increased DNA content and glycosaminoglycan amount in BMMSCs and ATMSCs, whereas SB203580 had little effect. Collagen type I (COL1A1) mRNA decreased to almost a quarter in BMMSCs treated with PD98059. The mRNA levels of collagen type II (COL2A1) and SRY (sex determining region Y)-box 9 (SOX-9) increased several fold in both cells after PD98059 treatment, whereas SB203580 had only a slight effect. The gene expression of collagen type X (COL10A1) and runt-related transcription factor 2 (Runx-2) decreased by half after PD98059 treatment in BMMSCs, and decreased further in ATMSCs. SB203580 elevated COL10A1 and Runx-2 gene expression in both cell types. Safranin-O staining and immunohistochemistry generally mirrored findings from real-time PCR except for diminished expression of type I collagen in ATMSCS, and more pronounced decrease in type X collagen and Runx-2 in BMMSCs after PD98059 treatment. Our study demonstrated that PD98059 suppressed hypertrophy and promoted chondrogenesis of MSCs, and provides a ground for using them in cartilage tissue engineering.
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PMID:The effects of ERK1/2 inhibitor on the chondrogenesis of bone marrow- and adipose tissue-derived multipotent mesenchymal stromal cells. 1980 53

The mitogen-activated protein kinases extracellular signal-regulated kinase (ERK)1 and 2 are essential intracellular mediators of numerous transmembrane signals. To investigate neural-specific functions of ERK2 in the brain, we used a Cre/lox strategy using Nestin:Cre to drive recombination in neural precursor cells. Nestin:Cre;ERK2(fl/fl) conditional knockout (cKO) mice have architecturally normal brains and no gross behavioral deficits. However, all cKO mice developed early-onset (postnatal day 35 to 40) frontal cortical astrogliosis, without evidence of neuronal degeneration. Frontoparietal cortical gray matter, but not underlying white matter, was found to contain abundant pericapillary and parenchymal reticulin fibrils, which were shown by immunohistochemistry to contain fibrillar collagens, including type I collagen. ERK1 general KO mice showed neither fibrils nor astrogliosis, indicating a specific role for ERK2 in the regulation of brain collagen. Collagen fibrils were also observed to a lesser extent in GFAP:Cre;ERK2(fl/fl) mice but not in CamKII-Cre;ERK2(fl/fl) mice (pyramidal neuron specific), consistent with a possible astroglial origin. Primary astroglial cultures from cKO mice expressed elevated fibrillar collagen levels, providing further evidence that the phenotype may be cell autonomous for astroglia. Unlike most other tissues, brain and spinal cord parenchyma do not normally contain fibrillar collagens, except in disease states. Determining mechanisms of ERK2-mediated collagen regulation may enable targeted suppression of glial scar formation in diverse neurological disorders.
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PMID:Brain-specific deletion of extracellular signal-regulated kinase 2 mitogen-activated protein kinase leads to aberrant cortical collagen deposition. 1989 51


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