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)

It has been shown that activation of protein tyrosine kinases (PTKs) is the earliest detectable signaling response to FcepsilonRI cross-linking on mast cells. Following tyrosine kinase activation, a family of mitogen-activated protein kinases (MAPKs) was found to be activated as well. Activation of this PTK signaling cascade will lead to mast cell degranulation. This review summarizes our recent studies on the role of PTK signaling cascade in an in vitro guinea pig model of allergic asthma using PTK inhibitors, genistein and tyrphostin 47, and MAPK kinase inhibitor, PD098059. Inhibitors of the PTK and MAPK signaling pathways significantly attenuated the ovalbumin (OVA)-induced bronchial anaphylactic contraction and enhanced relaxation of constricted airways, respectively, and substantially blocked the release of histamine and peptidoleukotrienes from chopped lung preparations induced by OVA. Based upon their substantial inhibitory effects on the Schultz-Dale reaction, further examination on the potential anti-asthmatic effects of PTK cascade inhibitors in an in vivo model of allergic asthma is recommended.
Asian Pac J Allergy Immunol 1999 Sep
PMID:Effects of inhibitors of the tyrosine kinase signaling cascade on an in vitro model of allergic airways. 1069 63

Despite the rapidly accumulating body of knowledge about protein networks, there is currently no convenient way of sharing and manipulation of such information. We suggest that a formal computer language for describing the biomolecular processes underlying protein networks is essential for rapid advancement in this field. We propose to model biomolecular processes by using the pi-Calculus, a process algebra, originally developed for describing computer processes. Our model for biochemical processes is mathematically well-defined, while remaining biologically faithful and transparent. It is amenable to computer simulation, analysis and formal verification. We have developed a computer simulation system, the PiFCP, for execution and analysis of pi-calculus programs. The system allows us to trace, debug and monitor the behavior of biochemical networks under various manipulations. We present a pi-calculus model for the RTK-MAPK signal transduction pathway, formally represent detailed molecular and biochemical information, and study it by various PiFCP simulations.
Pac Symp Biocomput 2001
PMID:Representation and simulation of biochemical processes using the pi-calculus process algebra. 1126 64

Unraveling the molecular mechanisms by which filarial nematodes, major human pathogens in the tropics, evade the host immune system remains an elusive goal. We have previously shown that excretory-secretory product-62 (ES-62), a homologue of phosphorylcholine-containing molecules that are secreted by human parasites and which is active in rodent models of filarial infection, is able to polyclonally activate certain protein tyrosine kinase and mitogen-activating protein kinase signal transduction elements in B lymphocytes. Such activation mediates desensitization of subsequent B cell Ag receptor (BCR) ligation-induced activation of extracellular signal-regulated kinase-mitogen-activated protein (ErkMAP) kinase and ultimately B cell proliferation. We now show that the desensitization is due to ES-62 targeting two major regulatory sites of B cell activation. Firstly, pre-exposure to ES-62 primes subsequent BCR-mediated recruitment of SHP-1 tyrosine phosphatase to abolish recruitment of the RasErkMAP kinase cascade via the Igalphabeta-ShcGrb2Sos adaptor complex interactions. Secondly, any ongoing ErkMAP kinase signaling in ES-62-primed B cells is terminated by the MAP kinase phosphatase, Pac-1 that is activated consequently to challenge via the BCR.
 ...
PMID:A filarial nematode-secreted phosphorylcholine-containing glycoprotein uncouples the B cell antigen receptor from extracellular signal-regulated kinase-mitogen-activated protein kinase by promoting the surface Ig-mediated recruitment of Src homology 2 domain-containing tyrosine phosphatase-1 and Pac-1 mitogen-activated kinase-phosphatase. 1139 Apr 99

Modulation of reactive oxygen species (ROS) plays a key role in signal transduction pathways. Selenoproteins act controlling the redox balance of the cell. We have studied how the alteration of the redox balance caused by patufet (selD(ptuf)), a null mutation in the Drosophila melanogaster selenophosphate synthetase 1 (sps1) gene, which codes for the SelD enzyme of the selenoprotein biosynthesis, affects the Ras/MAPK signalling pathway. The selD(ptuf) mutation dominantly suppresses the phenotypes in the eye and the wing caused by hyperactivation of the Ras/MAPK cassette and the activated forms of the Drosophila EGF receptor (DER) and Sevenless (Sev) receptor tyrosine kinases (RTKs), which signal in the eye and wing, respectively. No dominant interaction is observed with sensitized conditions in the Wnt, Notch, Insulin-Pi3K, and DPP signalling pathways. Our current hypothesis is that selenoproteins selectively modulate the Ras/MAPK signalling pathway through their antioxidant function. This is further supported by the fact that a selenoprotein-independent increase in ROS caused by the catalase amorphic Cat(n1) allele also reduces Ras/MAPK signalling. Here, we present the first evidence for the role of intracellular redox environment in signalling pathways in Drosophila as a whole organism.
 ...
PMID:Modulation of the Ras/MAPK signalling pathway by the redox function of selenoproteins in Drosophila melanogaster. 1178

The retinal determination (RD) gene network encodes a group of transcription factors and cofactors necessary for eye development. Transcriptional and posttranslational regulation of RD family members is achieved through interactions within the network and with extracellular signaling pathways, including epidermal growth factor receptor/RAS/mitogen-activated protein kinase (MAPK), transforming growth factor beta/DPP, Wingless, Hedgehog, and Notch. Here we present the results of structure-function analyses that reveal novel aspects of Eyes absent (EYA) function and regulation. We find that the conserved C-terminal EYA domain negatively regulates EYA transactivation potential, and that GROUCHO-SINE OCULIS (SO) interactions provide another mechanism for negative regulation of EYA-SO target genes. We have mapped the transactivation potential of EYA to an internal proline-, serine-, and threonine-rich region that includes the EYA domain 2 (ED2) and two MAPK phosphorylation consensus sites and demonstrate that activation of the RAS/MAPK pathway potentiates transcriptional output of EYA and the EYA-SO complex in certain contexts. Drosophila S2 cell two-hybrid assays were used to describe a novel homotypic interaction that is mediated by EYA's N terminus. Our data suggest that EYA requires homo- and heterotypic interactions and RAS/MAPK signaling responsiveness to ensure context-appropriate RD gene network activity.
 ...
PMID:Functional dissection of eyes absent reveals new modes of regulation within the retinal determination gene network. 1291 24

The most common type of renal injury in multiple myeloma is chronic tubulointerstitial nephropathy associated with casts in tubule lumens, an entity referred to as "myeloma kidney" that often progresses to end-stage kidney diseases. Myeloma kidney is associated with a significant increase in all-cause mortality, yet no effective intervention, except a limited use of steroid, is available. Here, we report that pituitary adenylate cyclase-activating polypeptide with 38 residues (PACAP38) dramatically prevents injury of cultured renal proximal tubule cells caused by myeloma light chains through suppression of proinflammatory cytokines production, by inhibiting p38 MAPK and translocation of NFkappaB via both PAC(1) and VPAC(1) receptors. The suppressive effects of PACAP was as effective as dexamethasone in all of their cytokine assays and demonstrated both in vitro and in vivo. Furthermore, PACAP38 inhibits myeloma cell growth directly and may also indirectly by suppressing production of the growth factor, IL-6, from bone marrow stromal cells, that is stimulated by adhesion of myeloma cells. These findings render PACAP38 worth evaluation as a promising candidate for an effective and safe renoprotectant in myeloma kidney, and possibly other nephropathy, and also as a new antitumor agent in multiple myeloma.
 ...
PMID:Potential protective action of pituitary adenylate cyclase-activating polypeptide (PACAP38) on in vitro and in vivo models of myeloma kidney injury. 1620 6

Mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase SHP-2, causes Noonan syndrome (NS), an autosomal dominant disorder with pleomorphic developmental abnormalities. Certain germline and somatic PTPN11 mutations cause leukemias. Mutations have gain-of-function (GOF) effects with the commonest NS allele, N308D, being weaker than the leukemia-causing mutations. To study the effects of disease-associated PTPN11 alleles, we generated transgenic fruitflies with GAL4-inducible expression of wild-type or mutant csw, the Drosophila orthologue of PTPN11. All three transgenic mutant CSWs rescued a hypomorphic csw allele's eye phenotype, documenting activity. Ubiquitous expression of two strong csw mutant alleles were lethal, but did not perturb development from some CSW-dependent receptor tyrosine kinase pathways. Ubiquitous expression of the weaker N308D allele caused ectopic wing veins, identical to the EGFR GOF phenotype. Epistatic analyses established that csw(N308D)'s ectopic wing vein phenotype required intact EGF ligand and receptor, and that this transgene interacted genetically with Notch, DPP and JAK/STAT signaling. Expression of the mutant csw transgenes increased RAS-MAP kinase activation, which was necessary but not sufficient for transducing their phenotypes. The findings from these fly models provided hypotheses testable in mammalian models, in which these signaling cassettes are largely conserved. In addition, these fly models can be used for sensitized screens to identify novel interacting genes as well as for high-throughput screening of therapeutic compounds for NS and PTPN11-related cancers.
 ...
PMID:Transgenic Drosophila models of Noonan syndrome causing PTPN11 gain-of-function mutations. 1639 95

Many chemopreventive agents appear to target signaling intermediates in apoptosis-inducing pathways. Inherently, the process of neoplastic conversion selects against apoptosis to initiate, promote, and perpetuate the malignant phenotype. Thus, targeting apoptosis pathways in pre-malignant cells, in which these pathways are still relatively intact, may be an effective module of cancer prevention. Diallyl sulfide (DAS), a naturally occurring organosulfide, present in garlic, is reported to have pleiotropic biological effects. DAS is known to inhibit chemically induced tumors in a number of in vivo and in vitro studies. The aberration of tumor suppressor gene, p53 and the ras oncogene have been linked to the induction of multiple signaling pathways and to the resistance offered by cancer cells to the apoptosis. Therefore, the present study was carried out to investigate the role of DAS on modulation of multiple p53 and ras-induced signaling pathways in 7,12-dimethylbenathacene (DMBA) induced skin carcinogenesis. The results showed that DAS up regulates expression of tumor suppressor protein p53 (wt p53) and its downstream target molecule p21/waf1. Proapoptotic protein, bax was upregulated by DAS supplementation. An opposite trend was observed in DMBA induced antiapoptotic proteins expressions, survivin and bcl-2, which were significantly downregulated by DAS supplementation. In the present study we also demonstrated that DAS supplementation significantly reduces the expression of ras oncoprotein and to modulate expression of its signaling molecules including PI3K/Akt and MAPKs. Western blot analysis demonstrated that DAS significantly reduced the DMBA induced protein expressions of PI3K/Akt and p38MAPK. However, DAS supplementation did not alter the expression JNK1 and ERK1/2. Thus, our results confirm that DAS can adopt a multi-prong strategy to target multiple signaling pathways leading to induction of apoptosis and inhibition of growth of DMBA induced skin tumors in Swiss albino mice. Although studies of single pathways have been helpful in guiding investigations, new tools to study the integration and multiplicity of signaling pathways hold the hope of improved understanding of the signaling pathway alterations in cancer chemoprevention by naturally occurring compounds.
Asian Pac J Cancer Prev
PMID:Involvement of multiple signaling pathways in diallyl sulfide mediated apoptosis in mouse skin tumors. 1725 Apr 26

The trophic neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) increases in many different neuron types following injury; a response postulated to support cell survival and regeneration. In acutely isolated cardiac ganglia, approximately 1% of the cardiac neurons exhibited PACAP immunoreactivity whereas after 72 h in culture, approximately 25% of the neurons were PACAP immunoreactive. In contrast, there was no increase in vasoactive intestinal polypeptide (VIP)-immunoreactive (IR) cells. Using a combination of immunocytochemical and molecular techniques, we have quantified PACAP expression, during explant culture of guinea-pig cardiac ganglia. Using real time polymerase chain reaction, PACAP transcript levels increased progressively up to 48 h in culture with no further increase after 72 h. PACAP transcript levels were reduced by neurturin at 48 h in culture but not after 24 or 72 h in culture. In addition, neurturin partially suppressed the percentage of PACAP-IR neurons after 72 h in culture, an effect mediated by activation of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase signaling pathways. The addition of different known regulatory molecules, including ciliary neurotrophic factor (CNTF), interleukin-1 beta (Il-1beta), tumor necrosis factor-alpha (TNFalpha), fibroblast growth factor basic (bFGF), transforming growth factor-beta (TGF-beta) and nerve growth factor (NGF) did not increase the percentage of PACAP-IR neurons after 24 h in culture; a result indicating that the generation and secretion of these factors did not stimulate PACAP expression. The presence of 20 nM PACAP or 10 muM forskolin increased the percentage of PACAP-IR cardiac neurons in 24 h cultures, but not in 72 h cultures. Neither treatment enhanced the number of VIP-IR neurons. The addition of the PACAP selective receptor (PAC(1)) receptor antagonist, M65 (100 nM) suppressed the 20 nM PACAP-induced increase in percentage of PACAP-IR cells in 24 h cultures indicating the effect of PACAP was mediated through the PAC(1) receptor. However, 100 nM M65 had no effect on the percentage of PACAP-IR cells in either 24 or 48 h cultures not treated with exogenous PACAP, suggesting that endogenous release of PACAP likely did not contribute to the enhanced peptide expression. We postulate that the enhanced PACAP expression, which occurs in response to injury is facilitated in the explant cultured cardiac ganglia by the loss of a target-derived inhibitory factor, very likely neurturin. In intact tissues the presence of neurturin would normally suppress PACAP expression. Lastly, our results indicate that many common trophic factors do not enhance PACAP expression in the cultured cardiac neurons. However, the stimulatory role of an, as yet, unidentified factor cannot be excluded.
 ...
PMID:Regulation of neuronal pituitary adenylate cyclase-activating polypeptide expression during culture of guinea-pig cardiac ganglia. 1736 46

Dietary components that are capable of inhibiting the growth of cancer cells without affecting the growth of normal cells are receiving considerable attention in developing novel cancer-preventive approaches. Tea, made from young leaves and leaf buds of the tea plant, 'Camellia sinensis', and the world's second most consumed beverage, has received a great deal of attention both from the general public and the scientific community because tea polyphenols are strong antioxidants, and tea preparations have inhibitory activity against tumorigenesis. Besides this, the wide spread consumption of tea throughout the world evoked the interest of the scientific community in the possibility of its use in cancer prevention. There are three main types of tea, all coming from the tea plant viz. black tea (fermented,) green tea (unfermented), or oolong tea (semi-fermented), classified based on the methods of brewing and processing. Inhibition of tumorigenesis by green or black tea preparations has been demonstrated in various animal models in different organs. Various epidemiological studies substantiate the correlation between tea consumption and cancer prevention; however, they have not yielded clear conclusions pertaining to the protective effects of tea consumption against cancer development in humans. Many mechanisms have been proposed for the inhibition of carcinogenesis by tea, including the modulation of signal transduction pathways (including growth factor-mediated, mitogen-activated protein kinase (MAPK)-dependent, and ubiquitin/proteasome degradation pathways ) that lead to the inhibition of cell proliferation and transformation; induction of apoptosis of preneoplastic and neoplastic cells, and inhibition of tumor invasion as well as angiogenesis. These mechanisms need to be evaluated, verified and corroborated in animal models and humans in order to gain more understanding on the effects of tea consumption on human cancer. Because the causative factors are different for different populations, tea consumption may affect carcinogenesis only in selected situations rather than having the general effect on all cancers. Although, on the basis of many epidemiological observations and numerous laboratory studies, it can be concluded that tea consumption is likely to have beneficial effects in reducing cancer risk in different populations, yet there is a need to define the population that could benefit from tea consumption. After careful evaluation of additional studies, it may be possible to recommend consumption of tea polyphenols by humans. Although considerable accumulating information provides a compelling body of evidence for the preventive potential of tea against cancer, naturally occurring tea polyphenols have yet to be evaluated in clinical intervention in human trials.
Asian Pac J Cancer Prev
PMID:Tea and cancer chemoprevention: a comprehensive review. 1769 25


1 2 3 4 5 6 7 8 Next >>