Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Little is known regarding the mitogen-activated protein kinase activation state in salivary gland adenoid cystic carcinoma. We evaluated the expression of the phosphorylated (activated) forms of the extracellular signal-regulated, C-jun N-terminal, and P38 kinases, as well as the Ki67 index by means of immunohistochemistry in archival paraffin-embedded material in 61 treatment-naive patients. Using a semiquantitative scoring methodology, we found that tumors were heterogeneous in their expression of phosphorylated mitogen-activated protein kinases. The rankings of scores for pairs of phosphorylated kinases across tumors were correlated (P < .01 in all comparisons). The correlation was strongest for phosphorylated P38 and C-jun N-terminal kinases (Kendall's tau, 0.39; 95% confidence interval, 0.21-0.57; P = .0007). Phosphorylated C-jun N-terminal kinases were associated with perineural invasion. In the 55 patients treated by surgery, high phosphorylated P38 (hazard ratio for death, 0.27; 95% confidence interval, 0.10-0.75; P = .01) and Ki67 (hazard ratio for death, 3.86; 95% confidence interval, 1.38-10.77; P = .01) could be used to fit a Cox regression model to overall survival. Our study provides evidence that mitogen-activated protein kinases are activated in adenoid cystic carcinoma and suggests that their activation is coordinated. High phosphorylated P38 levels predict for overall survival independently of tumor cell proliferation.
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PMID:Coordinated expression of activated mitogen-activated protein kinases in salivary gland adenoid cystic carcinoma. 1865 96

This review provides an overview of the molecular mechanisms of K transport in the mammalian connecting tubule (CNT) and cortical collecting duct (CCD), both nephron segments responsible for the regulation of renal K secretion. Aldosterone and dietary K intake are two of the most important factors regulating K secretion in the CNT and CCD. Recently, angiotensin II (AngII) has also been shown to play a role in the regulation of K secretion. In addition, genetic and molecular biological approaches have further identified new mechanisms by which aldosterone and dietary K intake regulate K transport. Thus, the interaction between serum-glucocorticoid-induced kinase 1 (SGK1) and with-no-lysine kinase 4 (WNK4) plays a significant role in mediating the effect of aldosterone on ROMK (Kir1.1), an important apical K channel modulating K secretion. Recent evidence suggests that WNK1, mitogen-activated protein kinases such as P38, ERK, and Src family protein tyrosine kinase are involved in mediating the effect of low K intake on apical K secretory channels.
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PMID:Regulation of potassium (K) handling in the renal collecting duct. 1883 6

NSC-741909 is a recently identified novel anticancer agent that suppresses the growth of several NCI-60 cancer cell lines with a unique anticancer spectrum. However, its molecular mechanisms remain unknown. To determine the molecular mechanisms of NSC-741909-induced antitumor activity, we analyzed the changes of 77 protein biomarkers in a sensitive lung cancer cell line after treatment with this compound by using reverse-phase protein microarray. The results showed that phosphorylation of mitogen-activated protein (MAP) kinases (P38 MAPK, ERK, and JNK) were persistently elevated by the treatment with NSC-741909. However, only the JNK-specific inhibitor SP600125 effectively blocked the apoptosis induced by NSC-741909. Moreover, NSC-741909-mediated apoptosis was also blocked by a dominant-negative JNK construct, suggesting that sustained activation of JNK is critical for the apoptosis induction. Further studies revealed that treatment with NSC-741909 suppressed dephosphorylation of JNK and the expression of MAPK phosphatase-1. Thus, NSC-741909-mediated inhibition of JNK dephosphorylation results in sustained JNK activation, which leads to apoptosis in cancer cells.
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PMID:Inhibiting JNK dephosphorylation and induction of apoptosis by novel anticancer agent NSC-741909 in cancer cells. 1941 86

The excessive proliferation and migration of synoviocytes are well-characterized phenomena that play key roles in the pathophysiology of rheumatoid arthritis (RA). Melatonin has been shown to have potent anti-proliferative effect in various cancer cells such as breast and prostate cancer cells. In this study, we examined the role of melatonin on synoviocyte proliferation in primary cultured human fibroblast-like synoviocytes (FLSs) by analyzing protein expression of P21(CIP1) (P21) and P27(KIP1) (P27), the cyclin-dependent kinase inhibitors that are important in cell cycle control, and the phosphorylation of mitogen-activated protein kinases (MAPKs). RA-FLS proliferation was determined by a [(3)H]-thymidine incorporation assay. Western blot analysis was applied to examine the underlying mechanisms of melatonin's effect. Melatonin inhibited RA-FLS proliferation in a dose-dependent manner. It reduced proliferation of passage 2 FLSs by 25% at 10 microm and by nearly 40% at 100 microm concentrations. The inhibitory effect of melatonin on RA-FLS proliferation was also observed in passages 4 and 6. Melatonin upregulated the expression levels of P21 and P27 dose-dependently (24 hr), induced the phosphorylation of extracellular signal-regulated protein kinase (ERK) time-dependently (10 microm), but did not affect phosphorylation of P38 in RA-FLSs. In addition, the expression of P21 and P27 triggered by melatonin was inhibited by the pretreatment of the ERK inhibitor, PD98059 (10 microm). The anti-proliferative action of melatonin in RA-FLSs was also blocked by PD98059. Taken together, these results suggest that melatonin exerts the inhibitory effect of the proliferation of RA-FLSs through the activation of P21 and P27 mediated by ERK. Hence we suggest that melatonin could be used as a therapeutic agent for the treatment of RA.
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PMID:Melatonin inhibits human fibroblast-like synoviocyte proliferation via extracellular signal-regulated protein kinase/P21(CIP1)/P27(KIP1) pathways. 1953 37

Human bone marrow mesenchymal stem cells (MSCs) are a potent source of growth factors, which are partly responsible for their beneficial paracrine effects. We reported previously that transforming growth factor-alpha (TGF-alpha), a putative mediator of wound healing and the injury response, increases the release of vascular endothelial growth factor (VEGF), augments tumor necrosis factor-alpha (TNF-alpha)-stimulated VEGF production, and activates mitogen-activated protein kinases and phosphatidylinositol 3-kinase (PI-3K) pathway in human MSCs. The experiments described in this report indicate that TGF-alpha increases MSC-derived hepatocyte growth factor (HGF) production. TGF-alpha-stimulated HGF production was abolished by inhibition of MEK, p38, PI-3K, or by small interfering RNA (siRNA) targeting TNF receptor 2 (TNFR2), but was not attenuated by siRNA targeting TNF receptor 1 (TNFR1). Ablation of TNFR1 significantly increased basal and stimulated HGF. A potent synergy between TGF-alpha and TNF-alpha was noted in MSC HGF production. This synergistic effect was abolished by MEK, P38, PI-3K inhibition, or by ablation of both TNF receptors using siRNA. We conclude that 1) novel cross talk occurs between tumor necrosis factor receptor and TGF-alpha/epidermal growth factor receptor in stimulating MSC HGF production; 2) this cross talk is mediated, at least partially, via activation of MEK, p38, and PI-3K; 3) TGF-alpha stimulates MSCs to produce HGF by MEK, p38, PI-3K, and TNFR2-dependent mechanisms; and 4) TNFR1 acts to decrease basal TGF-alpha and TNF-alpha-stimulated HGF.
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PMID:MEK, p38, and PI-3K mediate cross talk between EGFR and TNFR in enhancing hepatocyte growth factor production from human mesenchymal stem cells. 1969 52

Although cannabinoids exhibit a broad variety of anticarcinogenic effects, their potential use in cancer therapy is limited by their psychoactive effects. Here we evaluated the impact of cannabidiol, a plant-derived non-psychoactive cannabinoid, on cancer cell invasion. Using Matrigel invasion assays we found a cannabidiol-driven impaired invasion of human cervical cancer (HeLa, C33A) and human lung cancer cells (A549) that was reversed by antagonists to both CB(1) and CB(2) receptors as well as to transient receptor potential vanilloid 1 (TRPV1). The decrease of invasion by cannabidiol appeared concomitantly with upregulation of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). Knockdown of cannabidiol-induced TIMP-1 expression by siRNA led to a reversal of the cannabidiol-elicited decrease in tumor cell invasiveness, implying a causal link between the TIMP-1-upregulating and anti-invasive action of cannabidiol. P38 and p42/44 mitogen-activated protein kinases were identified as upstream targets conferring TIMP-1 induction and subsequent decreased invasiveness. Additionally, in vivo studies in thymic-aplastic nude mice revealed a significant inhibition of A549 lung metastasis in cannabidiol-treated animals as compared to vehicle-treated controls. Altogether, these findings provide a novel mechanism underlying the anti-invasive action of cannabidiol and imply its use as a therapeutic option for the treatment of highly invasive cancers.
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PMID:Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1. 1991 18

2',2',3',3',4',4',5',5',6',6',-decabrominated diphenyl ether (PBDE-209) is the most widely used polybrominated diphenyl ethers (PBDEs) globally. Some animal experiments have found that PBDE-209 caused developmental neurotoxicity. But detailed mechanisms are less well understood. Our experiments were conducted to research the potential neurotoxic mechanisms of PBDE-209 in primary cultured neonatal rat hippocampal neurons by measuring cell viability, apoptotic rate, expression of P38 mitogen-activated protein kinases (MAPKs), calcium ion concentration, oxidative stress, nitrous oxide (NO) content, and global gene DNA methylation levels. The neurons were exposed to different PBDE-209 concentrations (0, 10, 30 and 50 microg/ml). The difference between the experimental groups and control groups was significant (P<0.05). PBDE-209 increased the rate of apoptosis, expression of P38 MAPK, calcium ion concentration, reactive oxygen species (ROS) level, malondialdehyde (MDA) content and NO content (P<0.05). In addition, PBDE-209 deceased cell viability, activity of superoxide dismutase (SOD) and the levels of global gene DNA methylation (P<0.05). The results suggested that PBDE-209 could affect secondary messengers, cause oxidative stress and decrease global gene DNA methylation levels. These actions may contribute to the mechanism of PBDE-209 neurotoxicity.
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PMID:Assessment of the neurotoxic mechanisms of decabrominated diphenyl ether (PBDE-209) in primary cultured neonatal rat hippocampal neurons includes alterations in second messenger signaling and oxidative stress. 1994 12

Vascular smooth muscle cell (VSMC) apoptosis accelerates atherosclerosis and promotes restenosis following vascular injury. The current study examined the effects of cellular repressor of E1A-stimulated genes (CREG), a novel glycoprotein inhibiting transcription activation, on the regulation of VSMC apoptosis. Serum starvation or treatment of human VSMCs with apoptosis inducers (STS or VP-16) significantly reduced CREG expression and caused caspase-3 activation. CREG downregulation and caspase-3 activation were inversely related, suggesting that reduced CREG expression may contribute to VSMC apoptosis. Both loss-of-function (CREG-DW produced by retroviruses expressing CREG shRNAs) and gain-of-function (CREG-UP produced by retroviral infection with vector pLNCX-CREG) studies were performed to confirm this hypothesis. CREG-DW significantly increased VSMC apoptosis, whereas CREG-UP significantly reduced apoptosis. Moreover, p38 and JNK mitogen-activated protein kinases were significantly upregulated in CREG-DW and significantly reduced in CREG-UP VSMCs. More importantly, CREG-DW-induced VSMC apoptosis was blocked by the p38-specific inhibitor SB203580 or by overexpression of a dominant-negative P38 alpha (p38 alpha AGF). Balloon injury-induced vascular caspase-3 activation was significantly inhibited by treatment with recombinant CREG protein. These results demonstrated for the first time that CREG plays a key role in modulating VSMC apoptosis through the p38 and JNK signal transduction pathways, both in vitro and in situ.
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PMID:Cellular repressor of E1A-stimulated genes inhibits human vascular smooth muscle cell apoptosis via blocking P38/JNK MAP kinase activation. 2006 3

Signaling pathways mediate the effect of external stimuli on gene expression in cells. The signaling proteins in these pathways interact with each other and their phosphorylation levels often serve as indicators for the activity of signaling pathways. Several signaling pathways have been identified in mammalian cells but the crosstalk between them is not well understood. Alliance for Cellular Signaling (AfCS) has measured time-course data in RAW 264.7 macrophage cells on important phosphoproteins, such as the mitogen-activated protein kinases (MAPKs) and signal transducer and activator of transcription (STATs), in single- and double-ligand stimulation experiments for 22 ligands. In the present work, we have used a data-driven approach to analyze the AfCS data to decipher the interactions and crosstalk between signaling pathways in stimulated macrophage cells. We have used dynamic mapping to develop a predictive model using a partial least squares approach. Significant interactions were selected through statistical hypothesis testing and were used to reconstruct the phosphoprotein signaling network. The proposed data-driven approach is able to identify most of the known signaling interactions such as protein kinase B (Akt) --> glycogen synthase kinase 3alpha/beta (GSKalpha/beta) etc., and predicts potential novel interactions such as P38 --> RSK and GSK --> ezrin/radixin/moesin. We have also shown that the model has good predictive power for extrapolation. Our novel approach captures the temporal causality and directionality in intracellular signaling pathways. Further, case specific analysis of the phosphoproteins in the network has led us to propose hypothesis about inhibition (phosphorylation) of GSKalpha/beta via P38.
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PMID:Identification of crosstalk between phosphoprotein signaling pathways in RAW 264.7 macrophage cells. 2012 26

We have previously reported that gelsolin, an actin binding protein, regulates the fibrillization of amyloid-beta protein. We report here that the expression of cytoplasmic gelsolin (cgelsolin) was upregulated in a concentration-dependent manner when SH-SY5Y, PC-12, and HEK-293 cells were subjected to oxidative stress by treatment with hydrogen peroxide (H(2)O(2). Further studies were done to elucidate the mechanism involved in the regulation of c-gelsolin expression in cells. Pretreatment of cells with cycloheximide (an inhibitor of protein synthesis) resulted in significant inhibition of H(2)O(2)induced c-gelsolin expression, suggesting the possible de novo synthesis of c-gelsolin in cells. Staurosporine, a potent inhibitor of a variety of protein kinases including protein kinase C (PKC), also blocked the H(2)O(2)induced expression of cgelsolin. However, both H(2)O(2) and staurosporine activated the mitogen-activated protein kinases (MAPKs), i.e., c-Jun N-terminal kinase, P38, and extracellular signal-regulated kinase. Pretreatment of cells with Calphostin C, an inhibitor of PKC, blocked the upregulation of cgelsolin induced by H(2)O(2), while specific inhibitors of MAPKs had no effect on c-gelsolin expression, suggesting that MAPKs may not be involved in H(2)O(2)mediated upregulation of cgelsolin. On the other hand, phorbol-12-myristate-13-acetate, an activator of PKC, induced the expression of c-gelsolin. Our studies indicate that c-gelsolin is upregulated in cells under oxidative stress, and PKC is involved in its upregulation. It is suggested that activators of PKC that induce gelsolin expression may have therapeutic significance in Alzheimer's disease.
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PMID:Upregulation of cytoplasmic gelsolin, an amyloid-beta-binding protein, under oxidative stress conditions: involvement of protein kinase C. 2015 39


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