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)

Zinc porphyrins have anti-inflammatory and anti-allergic properties. The objective of the present study was to characterize the mechanism of zinc tetrakis-(N-methyl-4'-pyridyl) porphyrinato (ZnTMPyP) immune modulation by investigating its effects on the proliferative activity during thymocyte stimulation with mitogenic factors and the molecular events mediating thymocyte proliferation. The results indicate that ZnTMPyP inhibited thymocyte proliferation stimulated with various mitogenic factors, such as concanavalin A (Con A), interleukin (IL)-1beta, and lipopolysaccharide-exposed macrophage supernatant, in a concentration-dependent manner. ZnTMPyP was also effective in preventing DNA binding activity of nuclear factor kappaB (NF-kappaB) and IL-2 production by thymocytes in response to Con A or IL-1beta. Inhibition of p38 mitogen-activated protein kinase (MAPK) with SB203580 substantially inhibited Con A- or IL-1beta-induced DNA binding activity of NF-kappaB, whereas ZnTMPyP inhibited the activation of p38 MAPK. ZnTMPyP also inhibited Con A-induced chemiluminescence and tyrosine phosphorylation by thymocytes. In conclusion, our findings suggest that the antiproliferative effect of ZnTMPyP may be mediated by effective inhibition of the production of reactive oxygen species, tyrosine phosphorylation, p38 MAPK activation, NF-kappaB activation, and IL-2 production during mitogenic stimulation of thymocytes.
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PMID:Inhibition of mitogenic stimulant-induced activation of thymocytes with zinc tetrakis-(N-methyl-4'-pyridyl) porphyrinato. 1243 37

Cyclin D1 is essential for Neu-induced cell growth and is induced by growth factors through Ras-dependent and Ras-independent signaling pathways (1). Because flavopiridol, a novel flavanoid cyclin-cyclin-dependent kinase inhibitor, may function through Ras-dependent and/or -independent pathways, we hypothesized that treatment of breast cancer cells with inhibitors of Neu signaling and flavopiridol might synergize to inhibit proliferation. Human breast cancer cell lines, which express high levels of endogenous Neu receptor, were treated with the anti-Neu antibody, trastuzumab, together with flavopiridol and subject to MTT assay. Cell lines were assayed for alterations in cell cycle by fluorescence-activated cell sorter and signaling proteins by Western blot. Flavopiridol and trastuzumab synergistically inhibited DNA synthesis, cellular proliferation, and contact-dependent growth. Cytotoxic synergy was observed independent of the sequence of addition of the two drugs to cultured cells. In SKBR3 cells, a combination of trastuzumab and flavopiridol inhibited the Ras-MAPK-Akt pathway, decreased cyclin D1 abundance, and kinase activity to a greater extent than either drug alone. Compared with single-agent treatment, combination treatment selectively inhibited Akt and pRB phosphorylation. Cytotoxic synergy was observed with flavopiridol plus LY294002 (selective phosphatidylinositol 3-kinase inhibitor) but not with PD98059 (selective mitogen-activated protein kinase kinase 1 inhibitor) suggesting that Akt inhibition may be important in synergy. Zinc-induced overexpression of cyclin D1 in T-47D deltaMTcycD1 cells were more resistant to drug-induced cell death when compared with vector-transfected T-47D deltaMT cells. Cyclin D1 overexpression reverses drug treatment induced cell cycle arrest in SKBR3 cells. Flavopiridol and trastuzumab yield cytotoxic synergy in human breast cancer cells overexpressing Neu. Cyclin D1 overexpression results in combination drug resistance. In addition, inhibition of Akt may prove to be a useful therapeutic strategy in combination with flavopiridol.
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PMID:Flavopiridol and trastuzumab synergistically inhibit proliferation of breast cancer cells: association with selective cooperative inhibition of cyclin D1-dependent kinase and Akt signaling pathways. 1247 66

ANG II has been demonstrated to play a role in the progression of tubulointerstial injury. We studied the direct effect of ANG II on apoptosis of cultured rat renal proximal tubular epithelial cells (RPTECs). ANG II promoted RPTEC apoptosis in a dose- and time-dependent manner. This effect of ANG II was attenuated by anti-transforming growth factor (TGF)-beta antibody. Moreover, TGF-beta triggered RPTEC apoptosis in a dose-dependent manner. ANG II also enhanced RPTEC expression of Fas and Fas ligand (FasL); furthermore, anti-FasL antibody attenuated ANG II-induced RPTEC apoptosis. In addition, ANG II increased RPTEC expression of Bax, a cell death protein. Both ANG II type 1 (AT(1)) and type 2 (AT(2)) receptor blockers inhibited ANG II-induced RPTEC apoptosis. SB-202190, an inhibitor of p38 MAPK phosphorylation, and caspase-3 inhibitor also attenuated ANG II-induced RPTEC apoptosis. ANG II enhanced RPTEC heme oxygenase (HO)-1 expression. Interestingly, pretreatment with hemin as well as curcumin (inducers of HO-1) inhibited the ANG II-induced tubular cell apoptosis; conversely, pretreatment with zinc protoporphyrin, an inhibitor of HO-1 expression, promoted the effect of ANG II. These results suggest that ANG II-induced apoptosis is mediated via both AT(1) and AT(2) receptors through the generation of TGF-beta, followed by the transcription of cell death genes such as Fas, FasL, and Bax. Modulation of tubular cell expression of HO-1 has an inverse relationship with the ANG II-induced tubular cell apoptosis.
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PMID:Angiotensin II induces apoptosis in renal proximal tubular cells. 1252 53

Pyrrolidine dithiocarbamate (PDTC) is known to induce cell death by the stimulation of intracellular zinc transport and subsequent modulation of nuclear factor-kappaB (NF-kappaB) activity. Zinc is a signaling messenger that is released by neuronal activity at many central excitatory synapses. Excessive synaptic release of zinc followed by entry into vulnerable neurons contributes to severe neuronal cell death. In the present study, we explored how PDTC modulates intracellular signal transduction pathways, leading to neuronal cell death. The exposure of immortalized embryonic hippocampal cells (H19-7) to PDTC within the range of 1-100 microM caused cell death in a dose-dependent manner. During the cell death, NF-kappaB activity increased in response to PDTC, and this activity corresponded well with the increase of intracellular free zinc levels, implying that the activation of NF-kappaB transmits the cell death signals of PDTC. Furthermore, PDTC caused the activation of IkappaB kinase (IKK), casein kinase 2 (CK2), phosphatidylinositol 3-kinase (PI-3K), and Akt, as well as mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), but not p38 kinase. The blockade of PI-3K, JNK, and CK2 pathways resulted in a remarkable suppression of PDTC-induced cell death and also the activation of IKK, which subsequently led to a decrease of IkappaB phosphorylation. Although the overexpression of dominant-negative SEK in a transient manner did not inhibit the activation of Akt by PDTC, the transfection of kinase-inactive Akt mutants did cause a remarkable blockade of JNK activation, implying that Akt is present upstream of JNK in the PDTC-signaling pathways. Moreover, whereas selective CK2 inhibitors suppressed PDTC-induced JNK activation, the inhibition of JNK did not affect CK2 activity, suggesting that CK2 is directly related to the regulation of cell viability by PDTC and that the CK2-JNK pathway could be a downstream target of PDTC. Taken together, our results suggest that PDTC-mediated accumulation of intracellular zinc ions may affect cell viability by modulating several intracellular signaling pathways in neuronal hippocampal progenitor cells.
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PMID:Pyrrolidine dithiocarbamate-induced neuronal cell death is mediated by Akt, casein kinase 2, c-Jun N-terminal kinase, and IkappaB kinase in embryonic hippocampal progenitor cells. 1258 27

Tristetraprolin (TTP) is an mRNA-binding protein, but studies of this interaction have been difficult due to problems with the purification of recombinant TTP. In the present study, we expressed human and mouse TTP as glutathione S-transferase and maltose-binding protein (MBP) fusion proteins in Escherichia coli, and purified them by affinity resins and Mono Q chromatography. TTP cleaved from the fusion protein was identified by immunoblotting, MALDI-MS, and protein sequencing, and was further purified to homogeneity by continuous-elution SDS-gel electrophoresis. Purified recombinant TTP bound to the AU-rich element of tumor necrosis factor-alpha (TNFalpha) mRNA and this binding was dependent on Zn(2+). Results from sizing columns suggested that the active species might be in the form of an oligomer of MBP-TTP. Recombinant TTP was phosphorylated by three members of the mitogen-activated protein (MAP) kinase family, p42, p38, and JNK, with half-maximal phosphorylation occurring at approximately 0.5, 0.25, and 0.25 microM protein, respectively. Phosphorylation by these kinases did not appear to affect the ability of TTP to bind to TNFalpha mRNA under the assay conditions. This study describes a procedure for purifying nonfusion protein TTP to homogeneity, demonstrates that TTP's RNA-binding activity is zinc dependent, and that TTP can be phosphorylated by JNK as well as by the other members of the greater MAP kinase family.
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PMID:Expression and purification of recombinant tristetraprolin that can bind to tumor necrosis factor-alpha mRNA and serve as a substrate for mitogen-activated protein kinases. 1264 73

The single known epidermal growth factor-like growth factor and single epidermal growth factor receptor in Caenorhabditis elegans mediate two types of processes, each via a distinct signal transduction pathway. Several instances of cell fate specification during organogenesis require the RAS-MAP kinase pathway, as well as multiple nuclear factors. By contrast, appropriate myoepithelial contractions during ovulation involve IP3-mediated signal transduction. Positive modulators of the RAS pathway include KSR, SUR-8, phosphatase PP2A, and a zinc cation diffusion facilitator. Negative regulators of the RAS pathway include homologs of CBL, GAP-1, ACK, and MAP kinase phosphatase, while negative regulators of the IP3 pathway are enzymes that modify IP3. In addition to its stimulation of RAS activity, the GRB2 homolog SEM-5 acts negatively on both signaling pathways, as does the Ack-related kinase ARK-1.
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PMID:The epidermal growth factor system in Caenorhabditis elegans. 1264 74

It has been recently claimed that the human B1 receptors for kinins bind angiotensin-converting enzyme (ACE) inhibitors via a potential zinc-binding domain and are pharmacologically stimulated by these drugs. We verified whether ACE inhibitors stimulate B1 receptors in vitro. The isolated rabbit aorta or mouse stomach responded by negligible contractions to the application of captopril, enalaprilat, or zofenoprilat. The human isolated umbilical vein also failed to respond to enalaprilat. All of these preparations were responsive to the B1 receptor agonists des-Arg9-bradykinin (BK) or Lys-des-Arg9-BK. Furthermore, enalaprilat applied continuously had no significant interaction with the effects of Lys-des-Arg9-BK on the rabbit aorta. Enalaprilat failed to stimulate [3H]arachidonate release, translocate the receptors (confocal microscopy), or stimulate ERK1/2 phosphorylation (immunoblot) in HEK-293 cells stably expressing the rabbit B1 receptor conjugated to yellow fluorescent protein. The phospho-ERK1/2 content of arterial smooth muscle cells of human or rabbit origin was increased by treatment with Lys-des-Arg9-BK but not with enalaprilat. ACE inhibitors do not act as bona fide agonists of the kinin B1 receptors.
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PMID:Do angiotensin-converting enzyme inhibitors directly stimulate the kinin B1 receptor? 1264 80

Heme oxygenase-1 (HO-1) is the rate-limiting enzyme in heme catabolism, which leads to the generation of carbon monoxide (CO), biliverdin, and free iron. One of 3 mammalian HO isoforms, HO-1, is a stress-responsive protein and known to modulate such cellular functions as cytokine production, cell proliferation, and apoptosis to protect organs and tissues from acute injury. Although nitric oxide (NO)-mediated cytoprotective effects against cytotoxicity induced by glucose deprivation have been well recognized, the underlying mechanisms remain to be elucidated. Thus, we investigate the involvement of HO-1 in the cytoprotective effects of NO. Deprivation of glucose markedly reduced the viability of BNL CL.2 cells and primary rat hepatocytes. Pretreatment with NO donor, sodium nitroprusside (SNP), protected hepatocytes from glucose deprivation-induced cytotoxicity; zinc protoporphyrin (ZnPP) IX, an inhibitor of HO, was found to block the SNP-induced cytoprotection. SNP increased the induction of HO-1 protein as well as its activity in hepatocytes. A cytoprotective effect comparable to SNP was observed when the cells were transfected with HO-1 gene or preincubated with another HO-1 inducer, hemin. Additional experiments revealed the involvement of CO in the cytoprotective effect of SNP/HO-1 in BNL CL.2 cells. CO mediated cytoprotective effect through suppression of ERK MAPK activation. In conclusion, our results show that SNP protects hepatocytes from glucose deprivation-induced cytotoxicity through up-regulation of HO-1. Thus, HO-1 might be an important cellular target of NO donor with clinical implications for the prevention of acute liver injury in several pathological conditions.
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PMID:Nitric oxide-mediated cytoprotection of hepatocytes from glucose deprivation-induced cytotoxicity: involvement of heme oxygenase-1. 1266 64

The C(2)H(2) zinc-finger transcription factor Egr-1 has previously been shown to play an essential role within the endocrine system as a molecular determinant of LH beta-subunit synthesis in anterior pituitary gonadotrophs. The extent to which Egr-1 may be a dynamic mediator of changes in gonadotroph function during the oestrous cycle is currently unclear. We have recently produced a novel rat transgenic model of egr-1 gene function in which proximal regions of the rat egr-1 gene drive expression of a reporter gene. In the present study, we have investigated the expression and physiological regulation of our egr-1/d4 enhanced green fluorescent protein (EGFP) transgene in the female rat pituitary gland. In situ hybridization analysis has revealed anterior pituitary-specific expression that is limited to a sub-population of cells that includes immunohistochemically defined gonadotrophs. Expression of the transgene is up-regulated 5-fold following ovariectomy. The transgene also exhibits regulated expression during the oestrous cycle, mRNA levels being significantly raised on pro-oestrus. Using an explant culture system, we have also demonstrated a direct stimulatory effect of 17beta-oestradiol on anterior pituitary transgene and egr-1 expression. The acute response of egr-1 to an oestrogenic stimulus is attenuated by the MEK (MAPK kinase) inhibitor U0126, and is accompanied by increased levels of phospho-p44/42 MAPK protein, suggesting regulation of egr-1 through a MAPK-linked pathway in the pituitary. These findings provide further evidence of cyclical endocrine regulation of egr-1 in the rat, demonstrate that proximal sequences of the egr-1 gene mediate endocrine-regulated expression, and indicate a novel pathway through which pituitary transcriptional responses to oestrogen may be mediated.
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PMID:Oestrogenic regulation of an egr-1 transgene in rat anterior pituitary. 1268 42

The anthrax lethal factor (LF) is a Zn2+ endopeptidase specific for mitogen-activated protein kinase kinases (MAPKKs), which are cleaved within their N termini. Here, the proteolytic activity of LF has been investigated using novel chromogenic MAPKK-derived peptide substrates, which allowed us to determine the kinetic parameters of the reaction. LF displayed maximal proteolytic activity at the pH and temperature values of the cell cytosol, which is its site of action. LF undergoes substrate inhibition, in keeping with the non-productive binding geometry of the MAPPK-2 N terminus to LF.
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PMID:The metalloproteolytic activity of the anthrax lethal factor is substrate-inhibited. 1288 55


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