Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hypertrophic response is characterized by increased myofibril/sarcomere organization, induction of the cardiac specific atrial natriuretic factor (ANF) and myosin light chain-2 (MLC-2v) genes, and an increase in total cell volume. The alpha1-adrenergic agonist phenylephrine induces both the morphological and biochemical markers of hypertrophy in cultured neonatal rat ventricular cardiomyocytes. Previous studies have suggested a functional requirement for the heterotrimeric G-protein, Galphaq, for a subset of the hypertrophic phenotypes. The small GTPases Ras and Rho have also been implicated in phenylephrine-induced hypertrophy. To further delineate the role of Galphaq in hypertrophy, a constitutively active mutant of Galphaq was transiently transfected in primary rat ventricular cardiomyocytes. This molecule was sufficient to induce ANF-, AP1-, and MLC-2-driven gene expression. Co-transfection of Galphaq and dominant negative Ras or dominant negative Raf resulted in dose-dependent inhibition of ANF-driven expression. Both dominant negative Rho, and the Rho inhibitor C3-transferase, also attenuated Galphaq- and Ras-induced ANF-driven gene expression. Cells transfected with active Galphaq did not show a detectable increase in activation of the mitogen activated protein kinases ERK or SAPK. However, activity of the MAP-kinases appears to be important for Galphaq-induced gene expression since the MAP-kinase phosphatase Clone 100 and catalytically inactive SAPK strongly inhibited Galphaq-induced ANF expression. Thus, our studies indicate Galphaq-induced hypertrophic gene expression requires the small G-proteins Ras and Rho. The data also indicates that Galphaq mediated gene expression is dependent on functional MAP-kinases and that multiple signaling pathways contribute to Galphaq-mediated cardiac cell hypertrophy.
J Mol Cell Cardiol 1998 Mar
PMID:Ras and rho are required for galphaq-induced hypertrophic gene expression in neonatal rat cardiac myocytes. 951 26

The family of Tyr/Thr protein phosphatases, called dual-specificity phosphatases, have been implicated in the feedback regulation of the MAP kinase cascade by dephosphorylating the MAP kinases. Using low stringent cDNA screening we have isolated a chicken homologue of the CL100 phosphatase also called MAP kinase phosphatase 1 (MKP-1). The chicken MKP-1 has 84% and 85.5% identity to the rat and human amino acid sequence, respectively. Using RNase protection assay and in situ hybridization we have found that MKP-1 mRNA is expressed at low levels in most tissues during development. In embryonic dorsal root and sympathetic ganglia MKP-1 mRNA expression increases with age. The expression in large cells in dorsal root ganglia suggests that it is neurons which express MKP-1 mRNA. We also show that MKP-1 mRNA is induced in dissociated embryonic sympathetic neurons after nerve growth factor stimulation. In addition, our results show that MKP-1 mRNA is induced after NGF stimulation of fibroblasts expressing the NGF receptor TrkA, suggesting that MKP-1 is upregulated after activation of the TrkA receptor. These data show that the MKP-1 gene is regulated in a tissue and temporal specific fashion with strong expression in the developing peripheral ganglia, and suggest that the activation of MKP-1 mRNA expression by NGF is a ubiquitously induced response to TrkA activation, independent of the cellular origin or type on which the TrkA receptor is active.
Brain Res Mol Brain Res 1998 May
PMID:MAP kinase phosphatase-1 mRNA is expressed in embryonic sympathetic neurons and is upregulated after NGF stimulation. 960 44

Northern analyses of neonatal cardiac myocytes demonstrated that TGF-beta1 (5 ng/ml) stimulates and IL-1beta (5 ng/ml) decreases the steady-state levels of the mRNA coding for the Na+/Ca2+ exchanger. This is in agreement with the effects of TGF-beta1 and IL-1beta on beating rate and calcium uptake, suggesting that such effects might be mediated, at least partially, through up-regulation of the Na+/Ca2+ exchanger. Basal and TGF-beta1 stimulated mRNA levels were inhibited by the PKC inhibitors H7 (10 microM) and GF109203X (250 nM). In addition, apigenin (12.5 microM), a MAP kinase inhibitor, was able to inhibit basal mRNA levels for the exchanger. Cycloheximide (35.5 microM) had no effect on basal mRNA levels for the exchanger but steady-state levels were diminished in cells treated with TGF-beta1. Finally, actinomycin D (10 microM) inhibited both basal and TGF-beta1 stimulated mRNA levels, though with a more pronounced effect in the presence of TGF-beta1. These results suggest that a complex mechanism of regulation exists for the exchanger and that PKC and possibly MAP kinases might be involved. The up-regulation of this important protein for calcium extrusion, induced by TGF-beta1, might prepare cells to better overcome the calcium overload which occurs under cellular stress and might explain some of the cytoprotective effects of TGF-beta1.
Cell Mol Biol (Noisy-le-grand) 1998 May
PMID:TGF-beta1 up-regulates the mRNA for the Na+/Ca2+ exchanger in neonatal rat cardiac myocytes. 962 Apr 52

Long-term plasticity of the central nervous system (CNS) involves induction of a set of genes whose identity is incompletely characterized. To identify candidate plasticity-related genes (CPGs), we conducted an exhaustive screen for genes that undergo induction or downregulation in the hippocampus dentate gyrus (DG) following animal treatment with the potent glutamate analog, kainate. The screen yielded 362 upregulated CPGs and 41 downregulated transcripts (dCPGs). Of these, 66 CPGs and 5 dCPGs are known genes that encode for a variety of signal transduction proteins, transcription factors, and structural proteins. Seven novel CPGs predict the following putative functions: cpg2--a dystrophin-like cytoskeletal protein; cpg4--a heat-shock protein: cpg16--a protein kinase; cpg20--a transcription factor; cpg21--a dual-specificity MAP-kinase phosphatase; and cpg30 and cpg38--two new seven-transmembrane domain receptors. Experiments performed in vitro and with cultured hippocampal cells confirmed the ability of the cpg-21 product to inactivate the MAP-kinase. To test relevance to neural plasticity, 66 CPGs were tested for induction by stimuli producing long-term potentiation (LTP). Approximately one-fourth of the genes examined were upregulated by LTP. These results indicate that an extensive genetic response is induced in mammalian brain after glutamate receptor activation, and imply that a significant proportion of this activity is coinduced by LTP. Based on the identified CPGs, it is conceivable that multiple cellular mechanisms underlie long-term plasticity of the nervous system.
J Mol Neurosci 1998 Apr
PMID:Hippocampal plasticity involves extensive gene induction and multiple cellular mechanisms. 969 50

The expression of luteinizing hormone-releasing hormone (LHRH) and its receptors has been demonstrated in a number of human malignant tumors, including cancers of the breast, ovary, endometrium and prostate. These findings suggest the presence of an autocrine regulatory system based on LHRH. Recent studies in our laboratory have demonstrated that the function of LHRH produced by ovarian cancer cells is the inhibition of their proliferation. Dose-dependent antiproliferative effects of LHRH-agonists have been observed by several laboratories in cell lines derived from the above cancers. Interestingly, also LHRH-antagonists have marked antiproliferative activity in most of the ovarian, breast and endometrial cancer cell lines tested so far, indicating that the dichotomy of LHRH-agonists/LHRH-antagonists is not valid for the LHRH-system in cancer cells. In addition, our data suggest that the classical LHRH receptor signal transduction mechanisms known from the pituitary (phospholipase-C, protein kinase C, adenylyl cyclase) are not involved in the mediation of LHRH effects in cancer cells. Data obtained by several groups, including ours, rather suggest that LHRH analogs interfere with the signal transduction of growth-factor receptors and related oncogene products associated with tyrosine-kinase activity. The mechanism of action is probably an LHRH-induced activation of a phosphotyrosine phosphatase, counteracting the effects of receptor associated tyrosine kinase. In our hands, LHRH analogs virtually blocked the EGF-induced MAP-kinase activity of ovarian and endometrial cancer cells. The pharmacological exploitation of this mechanism might provide promising new therapies for these cancers.
J Steroid Biochem Mol Biol 1998 Apr
PMID:Effects of LHRH-analogues on mitogenic signal transduction in cancer cells. 969 74

Mammalian Cdc25 phosphatase is responsible for the dephosphorylation of Cdc2 and other cyclin-dependent kinases at Thr14 and Tyr15, thus activating the kinase and allowing cell cycle progression. The catalytic domain of this dual-specificity phosphatase has recently been mapped to the 180 most C-terminal amino acids. Apart from a CX3R motif, which is present at the active site of all known tyrosine phosphatases, Cdc25 does not share any obvious sequence similarity with any of those enzymes. Until very recently, the Cdc25 family was the only subfamily of tyrosine phosphates for which no three-dimensional structural data were available. Using the generalized profile technique, a sensitive method for sequence database searches, we found an extended and highly significant sequence similarity between the Cdc25 catalytic domain and similarly sized regions in other proteins: the non-catalytic domain of two distinct families of MAP-kinase phosphates, the non-catalytic domain of several ubiquitin protein hydrolases, the N and C-terminal domain of rhodanese, and a large and heterogeneous groups of stress-response proteins from all phyla. The relationship of Cdc25 to the structurally well-characterized rhodanese spans the entire catalytic domain and served as template for a structural model for human Cdc25a, which is fundamentally different from previously suggested models for Cdc25 catalytic domain organization. The surface positioning of subfamily-specific conserved residues allows us to predict the sites of interaction with Cdk2, a physiological target of Cdc25a. Based on the results of this analysis, we also predict that the budding yeast arsenate resistance protein Acr2 and the ORF Ygr203w encode protein phosphatases with catalytic properties similar to that of the Cdc25 family. Recent determination of the crystal structure of the Cdc25a catalytic domain supports the validity of the model and demonstrates the power of the generalized sequence profile technique in homology-based modeling of the three-dimensional structure of a protein having a weak but significant sequence similarity with a structurally characterized protein.
J Mol Biol 1998 Sep 11
PMID:A model of Cdc25 phosphatase catalytic domain and Cdk-interaction surface based on the presence of a rhodanese homology domain. 973 50

MAPK pathways transduce a broad variety of extracellular signals into cellular responses. Despite their pleiotropic effects and their ubiquitous distribution, surprisingly little is known about their involvement in the communication network of nerve cells. As a first step to elucidate the role of MAPK pathways in neuronal signalling, we studied the distribution of SAPK alpha/JNK2, SAPK beta/JNK3, and SAPK gamma/JNK1, three isoforms of SAPK/JNK, a stress-activated MAPK subfamily. We compared the mRNA localisation of the three main isoforms in the adult and developing rat brain using in situ hybridisation. In the adult brain, SAPK alpha and beta were widely but heterogeneously distributed, reproducing the pattern of a probe that does not discriminate the isoforms. Differently, high labelling for the SAPK gamma probe was exclusively localised in the endopiriform nucleus and medial habenula. Intermediate staining was detected in the hippocampus. During post-natal development, SAPK beta showed the same localisation as in the adult. Nevertheless, the semi-quantitative analysis of optical densities showed significantly different mRNA levels. In the adult, SAPK gamma signal was weak, whereas in newborn rats the labelling was intense and widely distributed. SAPK gamma mRNA levels decreased during development, to reach the low signals detected in the adult. These results suggest that in the central nervous system SAPK-type MAP kinases perform significant physiological functions which are particularly relevant during post-natal development. The distinct distribution patterns of SAPK isoforms in the adult rat brain support the hypothesis that separate functions are performed by the products of the three SAPK genes.
Brain Res Mol Brain Res 1998 Sep 18
PMID:Differential expression of SAPK isoforms in the rat brain. An in situ hybridisation study in the adult rat brain and during post-natal development. 974 3

Four glutathione S-transferase (GST, EC 2.5.1.18) isozymes have been characterized in the larvae of the diamondback moth (DBM), Plutella xylostella L., a cosmopolitan insect pest of crucifiers. This work aimed at cloning and heterologously expressing the cDNA of DBM GST-3, an isozyme involved in this insect resistance to some organophosphorus insecticides, and studying the molecular basis for its increased expression in the resistant strains. Reverse-transcription polymerase chain reaction (RT-PCR) using midgut mRNA from a methyl parathion resistant MPA strain and degenerate primers complimentary to the N-terminal and internal amino acid sequences of GST-3 generated a 128 bp DNA product. A clone of 809 bp, obtained by screening a midgut cDNA library of MPA strain using this PCR product as probe, encoded a protein of 216 amino acids (calculated Mr 24,083 and pI 8.50). This GST of DBM, PxGST3, shared the highest (46.3%) amino acid sequence identity, among insects, to MsGST1 of Manduca sexta. PxGST3 mRNA level was considerably higher in MPA than in susceptible strains, and Southern blots suggested that gene amplification was probably not involved in the increased expression of this GST isozyme. Enzymatically active PxGST3 expressed heterologously in E. coli exhibited similar biochemical and toxicological properties as GST-3 purified from DBM larvae. It is the first cloned GST with a well-defined role in insecticide resistance.
Insect Biochem Mol Biol 1998 Sep
PMID:Molecular cloning and heterologous expression of a glutathione S-transferase involved in insecticide resistance from the diamondback moth, Plutella xylostella. 975 75

Cardiac cellular hypertrophy plays an important role in cardiovascular diseases. Up until now, little has been known about the regulation of cellular growth on the level of intracellular signalling. Here, the implication of the p70(S6)-kinase (p70(S6K)) in the hypertrophic response after beta-adrenergic stimulation of cardiac myocytes from adult rats was investigated. Isoproterenol stimulation can activate p70(S6K) in adult cardiomyocytes analysed by direct kinase assays and retarded gel mobility. This signalling of beta-adrenoceptor stimulation is found only under conditions where the cardiomyocytes exhibit also a hypertrophic response to beta-adrenoceptor stimulation as measured by increase in protein content, RNA content and incorporation of radiolabelled amino acids. Rapamycin, a specific inhibitor of this kinase, reduces the trophic responses to control levels, suggesting an involvement of the p70(S6)-kinase in the development of cellular hypertrophy. An engagement of the MAP-kinase (ERK-1/2) pathway in the beta-adrenergic induced growth of cardiac myocytes from adult rats was excluded.
J Mol Cell Cardiol 1998 Oct
PMID:Activation of p70(S6) kinase by beta-adrenoceptor agonists on adult cardiomyocytes. 979 59

The structure of methionine aminopeptidase from hyperthermophile Pyrococcus furiosus (PfMAP) with an optimal growth temperature of 100 degreesC was determined by the multiple isomorphous replacement method and refined in three different crystal forms, one monoclinic and two hexagonal, at resolutions of 2.8, 2.9, and 3.5 A. The resolution of the monoclinic crystal form was extended to 1.75 A by water-mediated transformation to a low-humidity form, and the obtained diffraction data used for high-resolution structure refinement. This is the first description of a eukaryotic type methionine aminopeptidase structure. The PfMAP molecule is composed of two domains, a catalytic domain and an insertion domain, connected via two antiparallel beta-strands. The catalytic domain, which possesses an internal 2-fold symmetry and contains two cobalt ions in the active site, resembles the structure of a prokaryotic type MAP from Escherichia coli (EcMAP), while the structure of the insertion domain containing three helices has a novel fold and accounts for a major difference between the eukaryotic and prokaryotic types of methionine aminopeptidase. Analysis of the PfMAP structure in comparison with EcMAP and other mesophile proteins reveals several factors which may contribute to the hyperthermostability of PfMAP: (1) a significantly high number of hydrogen bonds and ion-pairs between side-chains of oppositely charged residues involved in the stabilization of helices; (2) an increased number of hydrogen bonds between the positively charged side-chain and neutral oxygen; (3) a larger number of buried water molecules involved in crosslinking the backbone atoms of sequentially separate segments; (4) stabilization of two antiparallel beta-strands connecting the two domains of the molecule by proline residues; (5) shortening of N and C-terminal tails and stabilization of the loop c3E by deletion of three residues.
J Mol Biol 1998 Nov 20
PMID:Crystal structure of methionine aminopeptidase from hyperthermophile, Pyrococcus furiosus. 981 45


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>