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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protection against ischemia by ischemic preconditioning (IP) is seen in many tissues and organs. However, the preconditioning ischemia must precede lethal ischemia for this effect to occur, and the creation of ischemia to treat heart disease does not seem to be a realistic strategy. Accordingly, the underlying mechanisms that confer cardioprotection should be identified. Early studies revealed that IP causes two windows of cardioprotection, and subsequent efforts to detect cardioprotective factors have identified various triggers, mediators, and potent effectors of IP, such as endogenous receptor agonists (adenosine, catecholamines, bradykinin, and opioids), intracellular messengers [protein kinase C (PKC), p38MAPK, PI-3K, and PKA], ion channels such as KATP channels, enzymes including heat shock proteins (HSPs), superoxide dismutase (SOD), and 5'-nucleotidase, and other factors [nitric oxide (NO), growth factors, free radicals, and products of the arachidonic acid cascade]. Some of these factors are involved in several different pathways and may have multiple roles in IP-induced cardioprotection. Recently, however, certain problems have arisen such as controversies related to increasing knowledge and the relative lack of clinical studies in contrast to the intensive performance of basic studies. To overcome these problems, the latest studies have followed three major trends: (1) investigation of mechanisms to explain the current controversies, (2) detection of other unknown potent mechanisms, and (3) promotion of clinical trials based on the evidence from experimental studies in larger animals. Here, we summarize recent investigations on IP, emphasizing on the controversial issues and emerging factors, and discuss current research on the prevention or treatment of ischemic heart disease including some relevant clinical studies.
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PMID:Ischemic preconditioning: emerging evidence, controversy, and translational trials. 1545 94

Several studies have shown antitumor activities of the melanoma differentiation-associated gene 7 (mda-7) and the nonsteroidal anti-inflammatory drug sulindac when used as a monotherapies against a wide variety of human cancers. However, the combined effects of mda-7 and sulindac have not previously been tested. Therefore, we tested the antitumor activity of an adenoviral vector expressing mda-7 (Ad-mda7) in combination with sulindac against non-small cell lung cancer cells in vitro and in vivo. When treated with Ad-mda7 in combination with sulindac, human lung cancer cells (A549 and H1299) underwent growth suppression resulting in apoptosis. The growth inhibition induced by Ad-mda7 in combination with sulindac was significantly greater than that observed with Ad-mda7 or sulindac alone. Furthermore, the degree of growth inhibition induced using this combination was dose-dependent for sulindac. Treatment with Ad-mda7 in combination with sulindac had no growth inhibitory effects on human normal lung (CCD-16) fibroblasts. We then investigated the mechanism by which sulindac enhances Ad-mda7-mediated apoptosis. Sulindac increased expression of ectopic MDA-7 protein in tumor cells, thereby increasing the expression of downstream effectors RNA-dependent protein kinase, p38MAPK, caspase-9, and caspase-3 and enhancing apoptosis of non-small cell lung cancer cells. Pulse-chase experiments showed that the increased expression of MDA-7 protein in sulindac-treated cells was due to increased half-life of the MDA-7 protein. Finally, treatment of human lung tumor xenografts in nude mice with Ad-mda7 plus sulindac significantly suppressed growth (P = 0.001) compared with Ad-mda7 or sulindac alone. Our results show for the first time that combined treatment with Ad-mda7 plus sulindac enhances growth inhibition and apoptosis of human lung cancer cells. The increased antitumor activity observed with the combination treatment is a result of increased half-life of MDA-7 protein. Regulation of protein turnover is a heretofore-unrecognized mechanism of this nonsteroidal anti-inflammatory drug.
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PMID:Sulindac enhances adenoviral vector expressing mda-7/IL-24-mediated apoptosis in human lung cancer. 1571

Amoebiasis caused by the protozoan parasite Entamoeba histolytica is one of the leading parasitic causes of morbidity and mortality in the developing countries. Among the variety of virulence factors, an adherence lectin (Gal/GalNAc, 260 kDa) has been known to mediate colonization and subsequent host responses. It is a major cell surface antigen which is universally recognized by the immune sera of patients with amoebic liver abscess (ALA). The role of this lectin in cytolysis and phagocytosis of human colonic mucin glycoproteins has also been established. The objective of the present study was to elucidate the signal transduction events induced in response to Entamoeba histolytica derived Gal/GalNAc lectin in the target epithelial cells. We have attempted to define a pathway in target cells that could link this immunodominant antigen to a known biological pathway for target cell activation and triggering of subsequent disease pathology/parasite survival. Lectin stimulated cells showed immediate rise in (Ca2+)i concentration corresponding to 1517.31+/-16.3 nM (approximately) at 0-2 min. The intracellular calcium also extruded from the cells as was measured by increase in calcium green-1 fluorescence. Expression of several protein kinases was checked by western blotting to delineate the signaling pathway. Results showed that the expression of PLA2, PI3K, Ras p21, Ras GAP, ERK-MAPK, p38MAPK and PKC was significantly increased. Expression of Raf-1 and MEK-1 was also found to be significant, as determined by intensity analysis. Overall, it indicated activation of MAPKinase pathway which is implicated in a variety of cellular functions. On the basis of our observations it can be stated that there is a calcium mediated activation of PKC in target cells, by lectin, which inturn activates cyclic nucleotides and other protein kinases. These protein kinases further phosphorylated downstream signals in a sequential manner, thus leading to the activation of MAPKinase cascade. Activation of MAPK cascade, in our studies, is implicated in a variety of physiological cellular functions including apoptosis, proliferation, cytoskeleton rearrangements and permeability changes. However, future screening of the genes responsible for the transcription and translation of new proteins and their biological functions in response to lectin stimulation will prove useful in understanding this host-parasite relationship.
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PMID:Activation of MAPK kinase pathway by Gal/GalNAc adherence lectin of E. histolytica: gateway to host response. 1572 42

The clinical application of rituximab (chimeric mouse anti-human CD20 mAb, Rituxan, IDEC-C2B8), alone and/or combined with chemotherapy, has significantly ameliorated the treatment outcome of patients with relapsed and refractory low-grade or follicular non-Hodgkin's lymphoma (NHL). The exact in vivo mechanisms of action of rituximab are not fully understood, although antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis have been suggested. We have proposed that modifications of the cellular signaling pathways by rituximab may be crucial for its clinical response. The B-cell restricted cell surface phosphoprotein CD20 is involved in many cellular signaling events including proliferation, activation, differentiation, and apoptosis upon crosslinking. Monomeric rituximab chemosensitizes drug-resistant NHL cells via selective downregulation of antiapoptotic factors through the type II mitochondrial apoptotic pathway. Several signaling pathways are affected by rituximab which are implicated in the underlying molecular mechanisms of chemosensitization. ARL (acquired immunodeficiency syndrome (AIDS)-related lymphoma) and non-ARL cell lines have been examined as in vitro model systems. In ARL, rituximab diminishes the activity of the p38MAPK signaling pathway resulting in inhibition of the interleukin (IL)-10/IL-10R autocrine/paracrine cytokine autoregulatory loop leading to the inhibition of constitutive STAT-3 activity and subsequent downregulation of Bcl-2 expression leading to chemosensitization. Rituximab upregulates Raf-1 kinase inhibitor protein (RKIP) expression in non-ARL cells. Through physical association with Raf-1 and nuclear factor kappaB (NF-kappa B)-inducing kinase (NIK), RKIP negatively regulates two major survival pathways, namely, the extracellular signal-regulated kinase1/2 (ERK1/2) and the NF-kappa B pathways, respectively. Downmodulation of the ERK1/2 and NF-kappa B pathways inhibits the transcriptional activity of AP-1 and NF-kappa B transcription factors, respectively, both of which lead to the downregulation of Bcl-(xL) (Bcl-2 related gene (long alternatively spliced variant of Bcl-x gene)) transcription and expression and sensitization to drug-induced apoptosis. Bcl-(xL)-overexpressing cells corroborated the pivotal role of Bcl-(xL) in chemosensitization. The specificity of rituximab-mediated signaling and functional effects were corroborated by the use of specific pharmacological inhibitors. Many patients do not respond and/or relapse and the mechanisms of unresponsiveness are unknown. Rituximab-resistant B-NHL clones were generated to investigate the acquired resistance to rituximab-mediated signaling, and chemosensitization. Resistant clones display different phenotypic, genetic and functional properties compared to wild-type cells. This review summarizes the data highlighting a novel role of rituximab as a signal-inducing antibody and as a chemosensitizing agent through negative regulation of major survival pathways. Studies presented herein also reveal several intracellular targets modified by rituximab, which can be exploited for therapeutic and prognostic purposes in the treatment of patients with rituximab- and drug-refractory NHL.
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PMID:Cellular and molecular signal transduction pathways modulated by rituximab (rituxan, anti-CD20 mAb) in non-Hodgkin's lymphoma: implications in chemosensitization and therapeutic intervention. 1578 36

Metastasis results from a sequence of selective events often involving interactions with elements of the tumor-specific physiological microenvironment. The low-serum component of this microenvironment confers increased motility and invasion in breast cancer cells by activating the Na+/H+ exchanger isoform 1 (NHE1). The present study was undertaken to characterize the signal transduction mechanisms underlying this serum deprivation-dependent activation of both the NHE1 and the concomitant invasive characteristics such as leading edge pseudopodia development and penetration of matrigel in breast cancer cell lines representing different stages of metastatic progression. Using pharmacological and genetic manipulation together with transport and kinase activity assays, we observe that the activation of the NHE1 and subsequent invasion by serum deprivation in metastatic human breast cells is coordinated by a sequential RhoA/p160ROCK/p38MAPK signaling pathway gated by direct protein kinase A phosphorylation and inhibition of RhoA. Fluorescence resonance energy transfer imaging of RhoA activity and immunofluorescence analysis of phospho-RhoA and NHE1 show that serum deprivation dynamically remodels the cell, forming long, leading edge pseudopodia and that this signal module is preferentially compartmentalized in these leading edge pseudopodia, suggesting a tight topographic relation of the signaling module to an invasion-specific cell structure.
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PMID:Protein kinase A gating of a pseudopodial-located RhoA/ROCK/p38/NHE1 signal module regulates invasion in breast cancer cell lines. 1584 33

We report here that staurosporine can induce apoptosis or differentiation of granulosa tumor cells depending on its dosage. In presence of staurosporine concentrations > 50 nM, apoptosis was triggered in human granulosa cell tumor cells COV434. In the presence of concentrations < 50 nM, the shape of the otherwise globular granulosa cells differentiated into a flattened epithelioid-like appearance. The process was associated by the induction of prostaglandin synthase-2 (PGS-2) and C/EBPbeta expression and by an increase in progesterone production in the supernatant culture medium. The observed effects of staurosporine were synergized by forskolin. With phosphorylation-specific Western blotting and protein kinase assays, it was demonstrated that staurosporine suppresses the phosphorylation of p38 and activates JNK. These results suggest that p38MAPK and JNK signal transduction pathways were involved in the regulation of granulosa cell differentiation by staurosporine. These results may indicate the usefulness of staurosporine or its analogs for the development of a future medical treatment of granulosa tumors.
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PMID:Apoptosis and differentiation induced by staurosporine in granulosa tumor cells is coupled with activation of JNK and suppression of p38 MAPK. 1587 Aug 72

Restriction of protein calories during stages of immaturity has a major influence on glucose metabolism and increases the risk of type 2 diabetes in adulthood. However, it is known that reduction of food intake alleviates insulin resistance. We previously demonstrated an improved insulin-induced glucose uptake in skeletal muscle of chronically undernourished adult rats. The purpose of this work was to investigate whether this condition is present during suckling, a period characterized by physiological insulin resistance as well as elucidate some of the underlying mechanisms. With this aim, 10-d-old pups from food-restricted dams were studied. We showed that undernourished suckling rats are glucose normotolerants, despite their depressed insulin secretion capacity. The content of the main glucose transporters in muscle, GLUT-4 and GLUT-1, was not affected by undernutrition, but fractionation studies showed an improved insulin-stimulated GLUT-4 translocation. p38MAPK protein, implicated in up-regulation of intrinsic activity of translocated GLUT-4, was increased. These changes suggest an improved insulin-induced glucose uptake associated with undernutrition. Insulin receptor content as well as that of both regulatory and catalytic phosphoinositol 3-kinase subunits was increased by food restriction. Insulin receptor substrate-1-associated phosphoinositol 3-kinase activity after insulin was enhanced in undernourished rats, as was phospho-glycogen synthase kinase-3, in line with insulin hypersensitivity. Surprisingly, protein tyrosine phosphatase-1B association with insulin receptor was also increased by undernutrition. These adaptations to a condition of severely limited nutritional resources might result in changes in the development of key tissues and be detrimental later in life, when a correct amount of nutrients is available, as the thrifty phenotype hypothesis predicts.
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PMID:Maternal food restriction enhances insulin-induced GLUT-4 translocation and insulin signaling pathway in skeletal muscle from suckling rats. 1590 22

Cyclooxygenase (COX)-2 expression in intestinal epithelial cells is associated with colorectal carcinogenesis. COX-2 expression is induced by numerous growth factors and gastrointestinal hormones through multiple protein kinase cascades. Here, the role of mitogen activated protein kinases (MAPKs) and small GTPases in COX-2 expression was investigated. Anisomycin and sorbitol induced COX-2 expression in non-transformed, intestinal epithelial IEC-18 cells. Both anisomycin and sorbitol activated p38(MAPK) followed by phosphorylation of CREB. SB202190 and PD169316 but neither PD98059 nor U0126 blocked COX-2 expression and CREB phosphorylation by anisomycin or sorbitol. Clostridium difficile toxin B inhibition of small GTPases did not affect anisomycin-induced COX-2 mRNA expression or phosphorylation of p38MAPK and CREB but did inhibit sorbitol-dependent COX-2 expression and phosphorylation of p38MAPK and CREB. Angiotensin (Ang) II-dependent induction of COX-2 mRNA and induced phosphorylation of p38MAPK and CREB were inhibited by toxin B. Reduction of CREB protein in cells transfected with CREB siRNAs inhibited anisomycin-induced COX-2 expression. These results indicate that activation of p38MAPK signaling is sufficient for COX-2 expression in IEC-18 cells. Ang II and sorbitol require small GTPase activity for COX-2 expression via p38MAPK while anisomycin-induced COX-2 expression by p38MAPK does not require small GTPases. This places small GTPase activity down-stream of the AT1 receptor and hyperosmotic stress and up-stream of p38MAPK and CREB.
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PMID:Anisomycin induces COX-2 mRNA expression through p38(MAPK) and CREB independent of small GTPases in intestinal epithelial cells. 1605 11

The neurite outgrowth inhibitor protein Nogo is one of 300 proteins that contain a reticulon homology domain, which is responsible for their association with the endoplasmic reticulum. Here we have found that the Nogo-B spliceform becomes phosphorylated at Ser107 in response to lipopolysaccharide in RAW264 macrophages or anisomycin in HeLa cells. The phosphorylation is prevented by SB 203580, an inhibitor of SAPK2a (stress-activated protein kinase 2a)/p38a and SAPK2b/p38b, and does not occur in embryonic fibroblasts generated from SAPK2a/p38a-deficient mice. Nogo-B is phosphorylated at Ser107 in vitro by MAPKAP-K2 [MAPK (mitogen-activated protein kinase)-activated protein kinase-2] or MAPKAP-K3, but not by other protein kinases that are known to be activated by SAPK2a/p38a. The anisomycin-induced phosphorylation of Ser107 in HeLa cells can be prevented by 'knockdown' of MAPKAP-K2 using siRNA (small interfering RNA). Taken together, our results identify Nogo-B as a new physiological substrate of MAPKAP-K2.
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PMID:Nogo-B is a new physiological substrate for MAPKAP-K2. 1609 39

One of three major families of the mitogen-activated kinases (MAPK), p38 as well as JNK, has been shown to transduce extracellular stress stimuli into cellular responses by phospho-relay cascades. Among p38 families, p38alpha is a widely characterized isoform and the biological phenomena are explained by its kinase activity regulating functions of its downstream substrates. However, its specific contributions to each phenomenon are yet not fully elucidated. For better understanding of the role of MAPKs, especially p38alpha, we utilized newly established mouse fibroblast cell lines originated from a p38alpha null mouse, namely, a parental cell line without p38alpha gene locus, knockout of p38alpha (KOP), Zeosin-resistant (ZKOP), revertant of p38alpha (RKOP), and Exip revertant (EKOP). EKOP is smaller in size but grows faster than the others. Although comparable amounts of ERK and JNK are expressed in each cell line, ERK is highly phosphorylated in EKOP even in normal culture conditions. Serum stimulation after serum starvation led to ERK phosphorylation in RKOP and ZKOP, but not in EKOP as much. On the contrary, relative phosphorylation level of JNK to total JNK in response to UV was low in RKOP. And its phosphorylation as well as total JNK is slightly lower in EKOP. RKOP is less sensitive to UV irradiation as judged by the survival rate. Stress response upon UV or sorbitol stimuli, leading to mitogen activate protein kinase activated kinase 2 (MAPKAPK2) phosphorylation, was only observed in RKOP. Further experiments reveal that MAPKAPK2 expression is largely suppressed in ZKOP and EKOP. Its expression was recovered by re-introduction of p38alpha. The loss of MAPKAPK2 expression accompanied by the defect of p38alpha is confirmed in an embryonic extract prepared from p38alpha null mice. These data demonstrate that p38 signal pathway is regulated not only by phosphorylation but also by modulation of the expression of its component. Together, we have established cell lines that can be used in analyzing the functions of MAPKs, especially p38alpha, and show that p38 is indispensable for MAPKAPK2 expression.
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PMID:p38 mitogen-activated protein kinase plays a key role in regulating MAPKAPK2 expression. 1619 17


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