Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.12 (PKG)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent work has demonstrated that endotoxin or cytokines induce nitric oxide synthase in heart or cardiac myocytes. We investigated the functional significance of inducible nitric oxide synthase (iNOS) in indo 1-loaded beating myocytes with regard to intracellular Ca2+ concentration ([Ca2+]i) and cell contraction. Lipopolysaccharide (LPS; 10 micrograms/ml) time dependently induced iNOS mRNA and protein in cultured neonatal rat cardiac myocytes. Nitrite concentration in the medium and intracellular guanosine 3',5'-cyclic monophosphate (cGMP) contents after 24-h exposure to LPS increased in proportion to the levels of iNOS induction in these cells. Myocytes treated with both NG-monomethyl-L-arginine and LPS for 24 h expressed iNOS protein, but nitrite production was significantly inhibited. Subsequent perfusion with 100-fold molar excess L-arginine of these myocytes elicited decreases in peak systolic [Ca2+]i (790 +/- 42 to 551 +/- 27 nM, P < 0.05), relative amplitude of cell contraction (100 to 72.4 +/- 5.5%, P < 0.05), and spontaneous beating rate (146 +/- 13 to 85 +/- 22 beats/min, P < 0.05). Pretreatment with methylene blue or KT-5823 inhibited these negative myocardial effects. These results suggest that LPS induces iNOS in cardiac myocytes and that the increased nitric oxide produced by iNOS has cardiac depressant effects through the activation of cGMP-dependent protein kinase.
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PMID:Cardiac inducible nitric oxide synthase negatively modulates myocardial function in cultured rat myocytes. 903 20

Chinese hamster ovary (CHO) cells become committed to initiate DNA replication at specific sites within the dihydrofolate reductase (DHFR) locus at a discrete point during G1 phase, the origin decision point (ODP). To better understand the requirements for passage through the ODP, we evaluated the ability of various inhibitors of G1-phase progression to prevent passage through the ODP. Of several protein kinase inhibitors tested, only inhibitors of cyclin-dependent kinase (cdk) activity (roscovitine, olomoucine) prevented passage through the ODP. Inhibitors of MAP kinase (PD98059), PKA (KT5720), PKG (KT5823), as well as inhibition of integrin-mediated signaling by preventing cell adhesion, all arrested cells in the post-ODP stages of G1 phase. Intriguingly, inhibitors of proteasome-dependent proteolysis (MG132, ALLN, lactacystin) and transcription (DRB, alpha-amanitin, actinomycin D) also inhibited passage through the ODP, whereas inhibition of protein synthesis (cycloheximide) had no effect on the ODP. Cross-checking each inhibitor for its affect on transcription revealed that the ODP could be uncoupled from transcription; MG132 and lactacystin did not inhibit transcription, and KT5720 was a potent inhibitor of transcription. Importantly, cells that were arrested upstream of the ODP with either roscovitine or lactacystin contained functional prereplication complexes (pre-RCs), supporting previous findings that pre-RC formation is not sufficient for origin specification. These results demonstrate that specification of the DHFR origin is independent of growth signaling mechanisms and does not require G1-phase synthesis of a protein regulator such as a cyclin or Dbf4/ASK1, positioning the ODP after pre-RC formation but prior to the activation of the known S-phase promoting kinases.
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PMID:Sensitivity of the origin decision point to specific inhibitors of cellular signaling and metabolism. 1179 46

The goals of this study were 2-fold: 1) to determine whether stimulation of Eph B4 receptors promotes microvascular endothelial cell migration and/or proliferation, and 2) to elucidate signaling pathways involved in these responses. The human endothelial cells used possessed abundant Eph B4 receptors with no endogenous ephrin B2 expression. Stimulation of these receptors with ephrin B2/Fc chimera resulted in dose- and time-dependent phosphorylation of Akt. These responses were inhibited by LY294002 and ML-9, blockers of phosphatidylinositol 3-kinase (PI3K) and Akt, respectively. Eph B4 receptor activation increased proliferation by 38%, which was prevented by prior blockade with LY294002, ML-9, and inhibitors of protein kinase G (KT5823) and MEK (PD98059). Nitrite levels increased over 170% after Eph B4 stimulation, indicating increased nitric oxide production. Signaling of endothelial cell proliferation appears to be mediated by a PI3K/Akt/endothelial nitric-oxide synthase/protein kinase G/mitogen-activated protein kinase cascade. Stimulation with ephrin B2 also increased migration by 63% versus controls. This effect was inhibited by blockade with PP2 (Src inhibitor), LY294002 or ML-9 but was unaffected by the PKG and MEK blockers. Eph B4 receptor stimulation increased activation of both matrix metalloproteinase-2 and -9. The results from these studies indicate that Eph B4 stimulates migration and proliferation and may play a role in angiogenesis.
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PMID:Eph B4 receptor signaling mediates endothelial cell migration and proliferation via the phosphatidylinositol 3-kinase pathway. 1223 51