Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth factors and cyclic AMP (cAMP) are known to activate distinct intracellular signaling pathways. Fibroblast growth factor (FGF) activates ras-dependent kinase cascades, resulting in the activation of MAP kinases, whereas cAMP activates protein kinase A. In this study, we report that growth factors and cAMP act synergistically to stimulate proenkephalin gene expression. Positive synergy between growth factor- and cAMP-activated signaling pathways on gene expression has not been previously reported, and we suggest that these synergistic interactions represent a useful model for analyzing interactions between these pathways. Transfection and mutational studies indicate that both FGF-dependent gene activation and cAMP-dependent gene activation require cAMP response element 2 (CRE-2), a previously characterized cAMP-dependent regulatory element. Furthermore, multiple copies of this element are sufficient to confer FGF regulation upon a minimal promoter, indicating that FGF and cAMP signaling converge upon transcription factors acting at CRE-2. Among many different ATF/AP-1 factors tested, two factors, ATF-3 and c-Jun, stimulate proenkephalin transcription in an FGF- or Ras-dependent fashion. Finally, we show that ATF-3 and c-Jun form heterodimeric complexes in SK-N-MC cells and that the levels of both proteins are increased in response to FGF but not cAMP. Together, these results indicate that growth factor- and cAMP-dependent signaling pathways converge at CRE-2 to synergistically stimulate gene expression and that ATF-3 and c-Jun regulate proenkephalin transcription in response to both growth factor- and cAMP-dependent intracellular signaling pathways.
 ...
PMID:Fibroblast growth factor and cyclic AMP (cAMP) synergistically activate gene expression at a cAMP response element. 793 70

We have identified a third member of the p38 group of MAP kinase termed p38 gamma. The cDNA for this MAP kinase encodes an 367 amino acid polypeptide that is slightly greater than 60% identical to p38 and p38 beta. Expression of its mRNA is primarily in muscle with no detectable expression in Northern blots using RNA from other tissues. In contrast to p38 and p38 beta, p38 gamma, fails to phosphorylate ATF-2 or MAPKAP kinase 2 but does like other MAP kinases phosphorylate MBP. In vivo kinase assays using protein extracts from skeletal muscle reveal that a 7-kDa protein is phosphorylated by p38 gamma but not by other members of this group of kinases. We suggest p38 gamma may have unique functions when compared with other members of the p38 group due to its restricted tissue expression and apparent substrate preferences.
 ...
PMID:The primary structure of p38 gamma: a new member of p38 group of MAP kinases. 892 Sep 15

A novel homologue of p38 MAP kinase, called SAPK4, has been cloned which shares 61% amino acid identity with p38 and is expressed predominantly in testes, pancreas and small intestine. We also cloned an alternative form of p38beta, termed p38beta2, which lacks the additional 8 amino acid insertion unique to p38beta. p38, p38beta, p38beta2, ERK6/p38gamma/SAPK3, and SAPK4 were characterized with respect to stimulus-dependent activation in transfected cells, substrate specificity, and sensitivity to inhibition by pyridinyl imidazoles. All homologues were stimulated, although to differing extents, by IL-1beta, TNF, sorbitol, and UV. Only SAPK3 and SAPK4 were stimulated significantly by PMA. p38beta showed the weakest activation overall. MBP, ATF-2, and both MAPKAP kinase-2 and kinase-3 were good substrates of p38 and p38beta in vitro. In contrast, only MBP, ATF2, and MAPKAP kinase-3 proved to be significant substrates of SAPK3 and SAPK4, and of these three, MAPKAP kinase-3 was by far the weakest. p38beta had very poor kinase activity for all substrates except MBP. While both p38 and p38beta2 were comparably inhibited by SB 203580 and SB 202190, neither SAPK3 nor SAPK4 were inhibited. p38beta was partially inhibited by both inhibitors. These data suggest that SAPK3 and SAPK4 form a distinct subset of the p38 MAP kinases with different expression pattern, response to stimuli, substrate specificity, and inhibitor sensitivity.
 ...
PMID:Novel homologues of CSBP/p38 MAP kinase: activation, substrate specificity and sensitivity to inhibition by pyridinyl imidazoles. 920 91

The involvement of serine/threonine protein phosphatases in signaling pathways that control the expression of the cyclooxygenase-2 (COX-2) gene in human chondrocytes was examined. Okadaic acid (OKA), an inhibitor of protein phosphatases 1 (PP-1) and 2A (PP-2A), induced a delayed, time-dependent increase in the rate of COX-2 gene transcription (runoff assay) resulting in increased steady-state mRNA levels and enzyme synthesis. The latter response was dose dependent over a narrow range of 1-30 nmol/L with declining expression and synthesis of COX-2 at higher concentrations due to cell toxicity. The delayed increase in COX-2 mRNA expression was accompanied by the induction of the proto-oncogenes c-jun, junB, junD, and c-fos (but not FosB or Fra-1). Increased phosphorylation of CREB-1/ATF-1 transcription factors was observed beginning at 4 h and reached a zenith at 8 h. Gel-shift analysis confirmed the up-regulation of AP-1 and CRE nuclear binding proteins, though there was little or no OKA-induced nuclear protein binding to SP-1, AP-2, NF-kappaB or NF-IL-6 regulatory elements. OKA-induced nuclear protein binding to 32P-CRE oligonucleotides was abrogated by a pharmacological inhibitor of protein kinase A (PKA), KT-5720; the latter compound also inhibited OKA-induced COX-2 enzyme synthesis. Calphostin C (CalC), an inhibitor of PKC isoenzymes, had little effect in this regard. Inhibition of 12P-CRE binding was also observed in the presence of an antibody to CREB-binding protein (265-kDa CBP), an integrator and coactivator of cAMP-responsive genes. The binding to 32P-CRE was unaffected in the presence of excess radioinert AP-1 and COX-2 NF-IL-6 oligonucleotides, although a COX-2 CRE-oligo competed very efficiently. 32P-AP-1 consensus sequence binding was unaffected by incubation of chondrocytes with KT-5720 or CalC, but was dramatically diminished by excess radioinert AP-1 and CRE-COX-2 oligos. Supershift analysis in the presence of antibodies to c-Jun, c-Fos, JunD, and JunB suggested that AP-1 complexes were composed of c-Fos, JunB, and possibly c-Jun. OKA has no effect on total cellular PKC activity but caused a delayed time-dependent increase in total PKA activity and synthesis. OKA suppressed the activity of the MAP kinases, ERK1/2 in a time-dependent fashion, suggesting that the Raf-1/MEKK1/MEK1/ERK1,2 cascade was compromised by OKA treatment. By contrast, OKA caused a dramatic increase in SAPK/JNK expression and activity, indicative of an activation of MEKK1/JNKK/SAPK/JNK pathway. OKA stimulated a dose-dependent activation of CAT activity using transfected promoter-CAT constructs harboring the regulatory elements AP-1 (c-jun promoter) and CRE (CRE-tkCAT). We conclude that in primary phenotypically stable human chondrocytes, COX-2 gene expression may be controlled by critical phosphatases that interact with phosphorylation dependent (e.g., MAP kinases:AP-1, PKA:CREB/ATF) signaling pathways. AP-1 and CREB/ATF families of transcription factors may be important substrates for PP-1/PP-2A in human chondrocytes.
 ...
PMID:Transcriptional induction of cyclooxygenase-2 gene by okadaic acid inhibition of phosphatase activity in human chondrocytes: co-stimulation of AP-1 and CRE nuclear binding proteins. 962 Jan 67

Apoptosis of arterial cells induced by oxidized low density lipoproteins (OxLDL) is thought to contribute to the progression of atherosclerosis. However, most data on apoptotic effects and mechanisms of OxLDL were obtained with extensively oxidized LDL unlikely to occur in early stages of atherosclerotic lesions. We now demonstrate that mildly oxidized LDL generated by incubation with oxygen radical-producing xanthine/xanthine oxidase (X/XO) induces apoptosis in primary cultures of human coronary endothelial and SMC, as determined by TUNEL technique, DNA laddering, and FACS analysis. Apoptosis was markedly reduced when X/XO-LDL was generated in the presence of different oxygen radical scavengers. Apoptotic signals were mediated by intramembrane domains of both Fas and tumor necrosis factor (TNF) receptors I and II. Blocking of Fas ligand (FasL) reduced apoptosis by 50% and simultaneous blocking of FasL and TNF receptors by 70%. Activation of apoptotic receptors was accompanied by an increase of proapoptotic and a decrease in antiapoptotic proteins of the Bcl-2 family and resulted in marked activation of class I and II caspases. Mildly oxidized LDL also activated MAP and Jun kinases and increased p53 and other transcription factors (ATF-2, ELK-1, CREB, AP-1). Inhibitors of Map and Jun kinase significantly reduced apoptosis. Our results provide the first evidence that OxLDL-induced apoptosis involves TNF receptors and Jun activation. More important, they demonstrate that even mildly oxidized LDL formed in atherosclerotic lesions may activate a broad cascade of oxygen radical-sensitive signaling pathways affecting apoptosis and other processes influencing the evolution of plaques. Thus, we suggest that extensive oxidative modifications of LDL are not necessary to influence signal transduction and transcription in vivo.
 ...
PMID:Mildly oxidized low density lipoprotein activates multiple apoptotic signaling pathways in human coronary cells. 1102 84

We previously showed that cepharanthine (CEP), a biscoclaurine alkaloid, induces caspase-dependent and Fas-independent apoptosis in Jurkat and K562 human leukemia cells. In the present study, we investigated the effect of CEP on three groups of human mitogen-activated protein kinases (MAPKs) in relation to CEP-induced apoptosis. CEP, at the concentration required for and at the time of induction of apoptosis, activated MAPKs p38 in both Jurkat and K562 cells and activated extracellular signal-regulated kinases (ERKs) only in K562 cells. However, CEP treatment did not trigger c-Jun NH(2)-terminal kinases (JNKs) activation. CEP increased the expression and phosphorylation levels of c-Jun and ATF-2 transcription factors. zVAD-fmk, a general caspase inhibitor, did not inhibit CEP-triggered p38 activation in Jurkat and K562 cells or ERK activation in K562 cells. Unexpectedly, pretreatment with a specific p38 inhibitor, SB203580, promoted CEP-induced apoptosis and caspase activation in Jurkat and K562 cells, whereas pretreatment with an MEK-1 inhibitor PD98059 inhibited CEP-induced apoptosis and caspase activation in K562 cells. A selective tyrosine kinase inhibitor, herbimycin A, which completely inhibited CEP-triggered ERKs activation, clearly promoted CEP-induced c-Jun expression and phosphorylation. Our results suggest that each of the three groups of MAP family members is uniquely involved in the CEP-mediated signal cascades in two different leukemia cell lines for inducing/regulating caspase activation and DNA fragmentation.
 ...
PMID:Modes of activation of mitogen-activated protein kinases and their roles in cepharanthine-induced apoptosis in human leukemia cells. 1189 91

Excitotoxicity is considered a major cell death inductor in neurodegeneration. Yet the mechanisms involved in cell death and cell survival following excitotoxic insults are poorly understood. Expression of active, phosphorylation-dependent mitogen-activated extracellular signal-regulated kinases (MAPK/ERKs), stress-activated c-Jun N-terminal kinases (SAPK/JNKs) and p38 kinases, as well as their putative active, phosphorylation-dependent specific transcriptional factor substrates CREB, Elk-1, ATF-2, c-Myc and c-Jun, has been examined following systemic administration of kainic acid (KA) at convulsant doses to rats. Increased phosphorylated MAPK (MAPK(P)) immunoreactivity has been found at 3 and 6 h in the vulnerable regions entorhinal cortex and CA3, in which neurons are committed to die, as well as in sensitive regions dentate gyrus and gyrus cinguli, in which neurons will survive. JNK(P) has been observed in the entorhinal cortex and dentate gyrus, and p38(P) immunoreactivity occurs in the entorhinal cortex. Strong c-Myc(P) expression parallels MAPK(P) immunoreactivity in the entorhinal cortex, CA3, dentate gyrus and gyrus cinguli, showing that enhanced c-Myc(P) expression does not preclude cell death or cell survival. Selective decrease of CREB(P) immunoreactivity in entorhinal cortex and CA3 indicates CREB(P) reduction associated with cell death. Strong c-Jun(P) immunoreactivity has been found in the entorhinal cortex, CA3 and dentate gyrus, thus suggesting that regulation of two opposing cellular programs (cell death or cell survival) of c-Jun(P) depends on c-Jun interactions with other factors. Interestingly, ATF-2(P), and to a lesser extent Elk-1(P), is selectively increased in the dentate gyrus. These results suggest ATF-2(P) involvement in cell survival of dentate gyrus granule cells. The present results demonstrate activation of specific MAPK pathways in association with either cell death or cell survival triggered by KA. Furthermore, increased Ras activation, as seen with p21 Ras activation assay, indicates a crucial role for Ras in activating MAP kinases following excitotoxic insult.
 ...
PMID:Active, phosphorylation-dependent MAP kinases, MAPK/ERK, SAPK/JNK and p38, and specific transcription factor substrates are differentially expressed following systemic administration of kainic acid to the adult rat. 1190 60

In eucaryotic cells reactive oxygen species (ROS) are produced in the reactions catalyzed by NAD(P)H oxidase and by some other specialized oxidases and also as an inevitable by-product of many redox reactions. Intracellular ROS synthesis is regulated by various hormones, cytokines, and growth factors. An increase in the ROS levels above a certain threshold (so-called oxidative stress) is accompanied by processes that are harmful for cell survival, such as lipid peroxidation and oxidative modification of proteins and nucleic acids. However, at low concentrations ROS act as secondary messengers responsible for a signal transduction from extracellular signaling molecules and their membrane receptors to the intracellular regulatory systems which control gene expression. Cellular transcriptional response to ROS is mediated mainly by activation of MAP protein kinases and submitted transcription factors AP-1, ATF, and NF-kappaB. A number of specific genes is also induced under hypoxia, i.e., under conditions opposite to oxidative stress. Cellular transcriptional response on hypoxia is mediated by activation of transcription factors HIF-1 and AP-1. Together with ROS, nitric oxide fulfills the role of a mobile and highly reactive redox-sensitive signaling molecule. Chemical reactions of NO with the superoxide anion and with other free radicals leads to production of highly reactive intermediates. Depending on the ratio of their intracellular concentrations, NO and ROS can either enhance or attenuate their reciprocal effects on cells.
 ...
PMID:Reactive oxygen species and regulation of gene expression. 1197 Jul 28

Theiler's murine encephalomyelitis virus (TMEV) infection of macrophages induces a demyelinating disease (DD) in certain strains of mice that is similar to human multiple sclerosis. In contrast to IFN-beta, expression of IL-23 p19 and p40 subunits by macrophages in response to TMEV may contribute to DD. TMEV infection of macrophages likely induces IL-23 and IFN-beta by activating p38 or ERK MAP-kinases (MAPK) and the p38 substrate ATF-2 within 30 min. To determine the role of MAPKs in TMEV-induced IL-23 and IFN-beta expression, RAW264.7 cells were pretreated with SB203580 or U0126, inhibitors of p38 and ERK MAPKs, respectively. SB203580 significantly increased TMEV-induced p19 but decreased p40 expression. In contrast, U0126 decreased p19 and increased TMEV-induced p40 and IFN-beta expression. Interestingly, U0126 prolonged TMEV-induced ATF-2 activation to at least 3h. Thus ERK MAPKs regulate expression of TMEV-induced p19 differently than p40 and IFN-beta suggesting the benefits of U0126 in treatment of DD.
 ...
PMID:ERK-MAP-kinases differentially regulate expression of IL-23 p19 compared with p40 and IFN-beta in Theiler's virus-infected RAW264.7 cells. 1562 75

Recently, it was demonstrated that the Varicella-zoster virus (VZV) infection led to an activation of MAP kinases. The viral protein encoded by ORF61 is a major effector of JNK/SAPK and p38/MAPK phosphorylation. ORF61 shows homology to HSV-1 ICP0, a multifunctional protein that influences the activity of c-Jun in infected cells. Stable expression of ORF61 in a MeWo derived cell line gave rise to two specific effects: (i) a major decrease of VZV replication and (ii) a strongly elevated basal JNK/SAPK phosphorylation but a reduced p38/MAPK phosphorylation, which were both altered following infection. A dose-dependent inhibition of JNK/SAPK in MeWo/61 cells resulted in a step-by-step increase of VZV replication. These findings indicate (i) that ORF61 is responsible for the elevated JNK/SAPK phosphorylation and (ii) that the VZV replication and the JNK/SAPK phosphorylation are related inversely. Compared to MeWo cells, the basal phosphorylation of downstream targets c-Jun and ATF-2 was reduced following ORF61 expression but restored after infection. Subsequent cascades to induce inflammatory responses were activated insignificantly; cascades to activate apoptotic events also remained silent. These data point towards an important role of ORF61 in the fine-regulation of activation of the MAPK pathways and their downstream targets to optimize the availability of cellular factors involved in VZV gene expression.
 ...
PMID:ORF61 protein of Varicella-zoster virus influences JNK/SAPK and p38/MAPK phosphorylation. 1590 10


1 2 Next >>