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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intestinal trefoil factor (ITF), a small, compact protease-resistant peptide, is abundantly expressed in goblet cells of large and small intestine. Although several biological activities of ITF have been identified, including promotion of wound healing, stimulation of epithelial cell migration, and protection of intestinal epithelial barrier, little is known about signaling events through which ITF mediates its physiological function. In this study, the effects of exogenous ITF on mitogen-activated protein kinase (MAPK) signaling cascades were examined in IEC-6 cells, a nontransformed intestinal epithelial cell line that does not express endogenous trefoil peptides. Stimulation with ITF resulted in rapid decrease in extracellular signal-related protein kinase (ERK) activity and concomitant reduced ERK tyrosine phosphorylation. ITF also decreased activation of ERK activity induced by either transforming growth factor-alpha, which links extracellular stimuli to the Ras/Raf/MEK/ERK pathway via the epidermal growth factor receptor, or phorbol 12-myristate 13-acetate, which activates Raf through protein kinase C. ITF-induced inhibition of ERK activity was blocked by an inhibitor of tyrosine and dual-specific phosphatases, sodium orthovanadate. In summary, ITF leads to inhibition of ERK and the MAPK pathway through activation of tyrosine or dual-specific phosphatase.
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PMID:Intestinal trefoil factor induces inactivation of extracellular signal-regulated protein kinase in intestinal epithelial cells. 941 49

Benzo[a]pyrene (B[a]P), a tobacco-derived carcinogen, induces lung tumors in rodents through its carcinogenic metabolite, anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]PDE). Tumorigenesis is inhibited by dietary myo-inositol in the post-initiation phase. However, little is known about how B[a]PDE and myo-inositol affect normal human lung cells. We addressed this question using untransformed human small airway epithelial (SAE) cells. SAE cell viability decreased <50% in parallel to an increase of apoptotic cells (>20%) 2 days after the cells were treated for 1 h with B[a]PDE (>100 nM). In contrast, the cell number and viability were not altered in A549 human lung cancer cells by B[a]PDE treatment up to 10 microM with <5% apoptotic cells and <10 U/l LDH in the medium. SAE cells retain the features of basal cells in serum-free, low Ca2+ (4 nM) medium up to 4-5 passages, but in serum-supplemented or serum-free, high Ca2+ (1 mM) cultures, they differentiate into non-ciliated epithelial cells expressing Clara cell secretory protein (CCSP). A non-toxic, physiologically relevant dose of B[a]PDE (1 nM) partially inhibited serum and Ca2+-induced SAE cell differentiation. This effect was abolished by wortmannin, a phosphatidylinositol-3 kinase (PI-3K) inhibitor, and PD98059, a mitogen activated protein kinase (MAPK) kinase-1 (MEK1) inhibitor, but not by SB202190, a p38 MAPK inhibitor, or melittin, a protein kinase C inhibitor. Myo-inositol (10-100 microM) did not alter growth or differentiation of untreated SAE or A549 cells, but reversed the inhibitory effect of B[a]PDE on serum and Ca2+-induced SAE cell differentiation when supplemented to the culture after B[a]PDE treatment. This myo-inositol action was not altered by PD98059, wortmannin or melittin, but was partially suppressed by SB202190. Collectively, these results indicate that B[a]PDE inhibits serum-induced SAE cell differentiation, possibly involving activating signals through a PI-3K/MEK1 mediated MAPK pathway, whereas myo-inositol protects SAE cells against this inhibitory effect of B[a]PDE perhaps through both PI-3K/MEK1 and p38 MAPK pathways.
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PMID:Effects of anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene on human small airway epithelial cells and the protective effects of myo-inositol. 993 61

The trefoil gene family of mucus cell-secreted proteins is a critical mediator of gastrointestinal mucosal restitution. Transcription of trefoil genes is induced during mucosal repair, but the regulatory mechanisms involved are unknown. Mice deficient in the intestine-specific peptide intestinal trefoil factor (ITF), in which colonic restitution is lethally impaired, showed reduced expression of the gastric trefoil genes SP and pS2, suggesting that trefoil peptides may individually regulate transcription of the entire family. In gastric cell lines, the trefoils were shown to act in a manner suggestive of immediate-early genes capable of auto- and cross-induction through cis-acting regulatory regions. Trefoil-mediated transcriptional regulation required activation of the Ras/MEK/MAP kinase signal transduction pathway. EGF receptor (EGF-R) activation was also necessary for trefoil auto- and cross-induction, and both spasmolytic polypeptide (SP) and ITF stimulation of gastric cell lines led to phosphorylation of EGF-R. Nevertheless, ITF and ITF-thioredoxin cell surface binding at 4 degrees C colocalized not with EGF-R, but with CD71, which is found in clathrin-coated pits, suggesting that integration of trefoil peptide responses may occur after internalization. As EGF-R expression is itself strongly induced after mucosal damage, the trefoil/EGF-R relationship may be pivotal in the generation and maintenance of the mucosal repair phenotype.
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PMID:The trefoil gene family are coordinately expressed immediate-early genes: EGF receptor- and MAP kinase-dependent interregulation. 1022 80

Cartducin, a paralog of Acrp30/adiponectin, is a secretory protein produced by both chondrogenic precursors and proliferating chondrocytes, and belongs to a novel C1q family of proteins. We have recently shown that cartducin promotes the growth of both mesenchymal chondroprogenitor cells and chondrosarcoma-derived chondrocytic cells in vitro. However, the cartducin-signaling pathways responsible for the regulation of cell proliferation have not been documented. In this study, we examined whether cartducin exists in serum and further investigated the intracellular signaling pathways stimulated by cartducin in mesenchymal chondroprogenitor cells. Western blot analysis showed that, unlike Acrp30/adiponectin, cartducin was undetectable in mouse serum. Next, mesenchymal chondroprogenitor N1511 cells were stimulated with cartducin, and three major groups of mitogen-activated protein kinase (MAPK) pathways and the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway were examined. Cartducin activated extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt, but not c-jun N-terminal kinase (JNK) nor p38 MAPK. The MEK1/2 inhibitor, U0126, blocked cartducin-stimulated ERK1/2 phosphorylation and suppressed the DNA synthesis induced by cartducin in N1511 cells. The PI3K inhibitor, LY294002, blocked cartducin-stimulated Akt phosphorylation and a decrease in cartducin-induced DNA synthesis in N1511 cells was also observed. These data suggest that cartducin is a peripheral skeletal growth factor, and that the proliferation of mesenchymal chondroprogenitor cells stimulated by cartducin is associated with activations of the ERK1/2 and PI3K/Akt signaling pathways.
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PMID:Cartducin stimulates mesenchymal chondroprogenitor cell proliferation through both extracellular signal-regulated kinase and phosphatidylinositol 3-kinase/Akt pathways. 1665 1

CTRP3/cartducin, a novel secretory protein, is a member of the C1q and tumor necrosis factor (TNF)-related protein (CTRP) superfamily. CTRP3/cartducin gene is transiently up-regulated in a balloon-injured rat carotid artery tissue. In this study, we report a new function of CTRP3/cartducin as a regulator of angiogenic processes. CTRP3/cartducin promoted proliferation and migration of mouse endothelial MSS31 cells in a dose-dependent manner. Further, stimulation of MSS31 by CTRP3/cartducin led to activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK). MAPK/ERK kinase 1/2 (MEK1/2) inhibitor, U0126, and p38 MAPK inhibitor, SB203580, blocked the CTRP3/cartducin-induced cell proliferation, and migration was blocked by U0126, but not the SB203580. Taken together, these results suggest that CTRP3/cartducin may be involved as a novel angiogenic factor in the formation of neointima following angioplasty.
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PMID:CTRP3/cartducin promotes proliferation and migration of endothelial cells. 1753 97

In this study, we report a novel gene, CCDC134 (coiled-coil domain containing 134), that encodes a secretory protein that can inhibit the MAPK pathway as a novel human MAPK-regulating protein. The CCDC134 mRNA contains 1280 nucleotides, encoding a protein of 229 amino acids. CCDC134 is a classical secretory protein. Expression profile analysis by Northern blot, RT-PCR, immunohistochemistry and Western blot reveals that CCDC134 is widely expressed in normal adult tissues, tumor tissues and cell lines. Functional investigation reveals that overexpression of CCDC134 and its purified protein significantly inhibit transcriptional activity of Elk1 and phosphorylation of Erk and JNK/SAPK but not p38 MAPK. Conversely, specific siRNA against CCDC134 activates Elk1 transcriptional activity and promotes Erk and JNK/SAPK phosphorylation. These results clearly indicate that CCDC134 is a novel member of the secretory family and down-regulates the Raf-1/MEK/ERK and JNK/ SAPK pathways.
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PMID:CCDC134, a novel secretory protein, inhibits activation of ERK and JNK, but not p38 MAPK. 1808 76

The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are phosphorylated after inhalation of asbestos. The effect of blocking this signaling pathway in lung epithelium is unclear. Asbestos-exposed transgenic mice expressing a dominant-negative mitogen-activated protein kinase kinase-1 (dnMEK1) (i.e., the upstream kinase necessary for phosphorylation of ERK1/2) targeted to lung epithelium exhibited morphologic and molecular changes in lung. Transgene-positive (Tg+) (i.e., dnMEK1) and transgene-negative (Tg-) littermates were exposed to crocidolite asbestos for 2, 4, 9, and 32 days or maintained in clean air (sham controls). Distal bronchiolar epithelium was isolated using laser capture microdissection and mRNA analyzed for molecular markers of proliferation and Clara cell secretory protein (CCSP). Lungs and bronchoalveolar lavage fluids were analyzed for inflammatory and proliferative changes and molecular markers of fibrogenesis. Distal bronchiolar epithelium of asbestos-exposed wild-type mice showed increased expression of c-fos at 2 days. Elevated mRNA levels of histone H3 and numbers of Ki-67-labeled proliferating bronchiolar epithelial cells were decreased at 4 days in asbestos-exposed Tg+ mice. At 32 days, distal bronchioles normally composed of Clara cells in asbestos-exposed Tg+ mouse lungs exhibited nonreplicating ciliated and mucin-secreting cells as well as decreased mRNA levels of CCSP. Gene expression (procollagen 3-a-1, procollagen 1-a-1, and IL-6) linked to fibrogenesis was also increased in lung homogenates of asbestos-exposed Tg- mice, but reduced in asbestos-exposed Tg+ mice. These results suggest a critical role of MEK1 signaling in epithelial cell proliferation and lung remodeling after toxic injury.
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PMID:Targeting the MEK1 cascade in lung epithelium inhibits proliferation and fibrogenesis by asbestos. 1819

CTRP3/cartducin, a novel secretory protein, is a member of the C1q and tumor necrosis factor (TNF)-related protein (CTRP) superfamily, and plays important roles in regulating both embryonic cartilage development and postnatal longitudinal bone growth. CTRP3/cartducin is expressed in human osteosarcomas. We hypothesized that CTRP3/cartducin might have a role in osteosarcoma tumor growth and metastasis. Murine osteosarcoma cell lines, NHOS and LM8, were used as a model. RT-PCR analysis showed that the mRNA level of CTRP3/cartducin was increased in these two murine osteosarcoma cell lines compared with its level in normal murine osteoblast MC3T3-E1 cells. Western blot analysis showed that the protein level of CTRP3/cartducin was also increased in these two osteosarcoma cell lines. Stimulation of NHOS and LM8 cells by CTRP3/cartducin promoted tumor cell growth but not migration in vitro. Further, CTRP3/cartducin stimulation led to the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in these two osteosarcoma cell lines. MAPK/ERK kinase 1/2 (MEK1/2) inhibitor, U0126, blocked CTRP3/cartducin-induced cell proliferation. These results suggest that CTRP3/cartducin expression may play a role in osteosarcoma tumor growth associated with activation of the ERK1/2 signaling pathway.
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PMID:Elevated expression of CTRP3/cartducin contributes to promotion of osteosarcoma cell proliferation. 1942 26

Mature Nicotiana benthamiana shows strong resistance to the potato late blight pathogen Phytophthora infestans. By screening using virus-induced random gene silencing, we isolated a gene for plant-specific calreticulin NbCRT3a as a required gene for resistance of N. benthamiana against P. infestans. NbCRT3a encodes an endoplasmic reticulum quality-control (ERQC) chaperone for the maturation of glycoproteins, including glycosylated cell-surface receptors. NbCRT3a-silenced plants showed no detectable growth defects but resistance to P. infestans was significantly compromised. Defense responses induced by the treatment with INF1 (a secretory protein of P. infestans), such as production of reactive oxygen species and accumulation of phytoalexins, were suppressed in NbCRT3a-silenced N. benthamiana. Expression of an ethylene-regulated gene for phytoalexin biosynthesis, NbEAS, was reduced in NbCRT3a-silenced plants, whereas the expression of salicylic acid-regulated NbPR-1a was not affected. Consistently, induction of ethylene production by INF1 was suppressed in NbCRT3a-silenced plants. Resistance reactions induced by a hyphal wall components elicitor prepared from P. infestans were also impaired in NbCRT3a-silenced plants. However, cell death induced by active mitogen-activated protein kinase kinase (NbMEK2(DD)) was not affected by the silencing of NbCRT3a. Thus, NbCRT3a is required for the initiation of resistance reactions of N. benthamiana in response to elicitor molecules derived from P. infestans.
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PMID:Nicotiana benthamiana calreticulin 3a is required for the ethylene-mediated production of phytoalexins and disease resistance against oomycete pathogen Phytophthora infestans. 2361 17

Intestinal trefoil factor (ITF), a member of the trefoil factor family, is a "Super-protective factor" for intestinal mucosal protection. This study was designed to explore the mechanism by which ITF promotes intestinal epithelial cell migration. Intestinal epithelial cells were treated with the human ITF (hITF). Phospho-ERK, phospho-STAT3 Tyr(705), and phospho-STAT3 Ser(727) levels were detected at different time points by western blot. To assess the potential crosstalk between the ERK and JAK/STAT3 pathways, HT-29 cells were treated with the MEK-inhibitor, U0126, and phosphor-STAT3 levels were evaluated. Conversely, cells were treated with the JAK-inhibitor, AG490, and ERK-activity was evaluated. Transwell assay was performed to investigate the effect of the crosstalk on the cell motility. MMP-2 and MMP-9 transcription was analyzed by quantitative real-time PCR. E-cadherin degradation was detected by immunofluorescence. Our results indicate that hITF simultaneously activated the ERK and JAK/STAT3 pathways and a crosstalk was detected between the two pathways. hITF increased cell migration. This effect was abolished by U0126 and AG490 treatment. hITF increased MMP2 and MMP9 mRNA levels and E-cadherin degradation and U0126 and AG490 abolished this effect of hITF. In conclusion, the hITF-induced crosstalk between the ERK and JAK/STAT3 pathways is associated with intestinal epithelial cell migration.
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PMID:ITF promotes migration of intestinal epithelial cells through crosstalk between the ERK and JAK/STAT3 pathways. 2761 44


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