Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.11 (AMPK)
 12,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of the classical mitogen-activated protein kinase (MAPK) pathway leads to proliferation of many cell types. Accordingly, an inhibitor of MAPK kinase, PD 098059, inhibits PDGF-induced proliferation of human arterial smooth muscle cells (SMCs) that do not secrete growth-inhibitory PGs such as PGE2. In striking contrast, in SMCs that express the inducible form of cyclooxygenase (COX-2), activation of MAPK serves as a negative regulator of proliferation. In these cells, PDGF-induced MAPK activation leads to cytosolic phospholipase A2 activation, PGE2 release, and subsequent activation of the cAMP-dependent protein kinase (PKA), which acts as a strong inhibitor of SMC proliferation. Inhibition of either MAPK kinase signaling or of COX-2 in these cells releases them from the influence of the growth-inhibitory PGs and results in the subsequent cell cycle traverse and proliferation. Thus, the MAPK pathway mediates either proliferation or growth inhibition in human arterial SMCs depending on the availability of specific downstream enzyme targets.
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PMID:The mitogen-activated protein kinase pathway can mediate growth inhibition and proliferation in smooth muscle cells. Dependence on the availability of downstream targets. 925 87

The intracellular signal transduction pathways utilized by the HIV-1-derived protein, Tat, in the activation of human central nervous system-derived endothelial cells (CNS-ECs) were examined using specific enzymatic assays. Tat induced an increase in interleukin 6 (IL-6) mRNA within 1 hr of treatment. This biological effect of Tat involved activation of both protein kinase C (PK-C) and cAMP-dependent protein kinase (PK-A) in CNS-ECs. Tat at 10 ng/ml induced a sharp, transient increase in membrane PK-C activity within 30 sec of incubation, and reached maximum levels at 2 min, declining to control values within 10 min. Tat also induced a sharp increase in intracellular cAMP levels and PK-A activity in these cells, with the PK-A activity reaching a maximum at 10 min and slowly declining to control values in 4 hr of incubation. Activation of PK-A was dependent on a Tat-induced increase in membrane PK-C activity as demonstrated by calphostin C (a PK-C inhibitor) abolishing this effect. Incubation of cells with the cyclooxygenase inhibitor indomethacin did not affect Tat-induced activation of PK-A, indicating that prostacyclins are not involved in this process. Tat-induced increase in IL-6 mRNA was abolished in the presence on PK-A inhibitor H-89, demonstrating that activation of PK-A is necessary and sufficient for the increase in IL-6 production by these cells. Both the Tat-induced increase in intracellular cAMP and IL-6 mRNA levels in CNS-ECs may play a role in altering the blood-brain barrier and thereby inducing pathology often observed in AIDS dementia.
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PMID:Human immunodeficiency virus Tat protein induces interleukin 6 mRNA expression in human brain endothelial cells via protein kinase C- and cAMP-dependent protein kinase pathways. 967 Dec 11

The effects of 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine H-7 (a cAMP-dependent protein kinase and protein kinase C inhibitor), n-(2-[methylamino]ethyl)-5-isoquinoline-sulfonamide H-8 (a cAMP- and cGMP-dependent protein kinase inhibitor) and indomethacin (IND, a cyclooxygenase inhibitor) on both the spontaneous metastatic ability of 3LL (Lewis lung carcinoma) tumor cells and anti-tumor host response were studied. The study of tumor progression showed that H-7 and H-8 (2 mg kg(-1) day(-1) , i.p., for 8 days) significantly reduced the mean number of metastases (0.8 +/- 0.2 and 1.0 +/- 0.7, respectively, P < 0.05) with respect to the number of lung metastases (4.2 +/- 2.1) observed in the control group. In turn, the highest tumor-specific cytotoxicity response (50% increase vs. non-treated target cells) was observed when both animal and tumor cells were treated with H-8. This suggests that the protein kinase inhibitors could inhibit tumor progression toward lung metastases formation by blocking the immunosuppressor mechanism triggered by agents that increase intracellular cAMP.
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PMID:Effect of the protein kinase inhibitors, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine H-7 and N-(2-[methylamino]ethyl)-5-isoquinoline-sulfonamide H-8 on Lewis lung carcinoma tumor progression. 972 36

Endothelin (ET-1), a contractor and mitogen in the vasculature, enhanced cAMP production (t1/2, 2.2 min; EC50, 89 +/- 6.3 nM) and stimulated activity of the cAMP-dependent protein kinase (PKA) in pig coronary arteries. These responses were blunted by the protein tyrosine kinase (PTK) inhibitors genistein and herbimycin-A, but not by inhibitors of protein kinase C or cyclooxygenase. In contrast, forskolin-stimulated cAMP production was unaffected by PTK inhibition. Immunoblot analysis revealed that ET-1 induced a concentration-dependent protein tyrosine (PT) phosphorylation. Sarafotoxin-c, a selective ETB receptor agonist, had no effect on either cAMP levels or PT phosphorylation. Moreover, pervanadate (PV), a potent inhibitor of PT phosphatases, enhanced both cAMP formation and PT phosphorylation, both of which were blocked by PTK inhibitors. The effects of ET-1 and PV were not additive, suggesting a similar mode of activation, whereas responses to ET-1 and forskolin were synergistic. These findings indicate that AC and PKA are activatable via a nonreceptor PTK-dependent pathway downstream from the G-protein-linked ETA receptor. Because cAMP is a dilator and antimitogen in smooth muscle, stimulation of AC activity may be a negative feedback mechanism regulating ET-1-induced vasoconstriction and/or mitogenesis.
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PMID:Evidence for a tyrosine kinase-dependent activation of the adenylyl Cyclase/PKA cascade downstream from the G-protein-linked endothelin ETA receptor in vascular smooth muscle. 979 2

In serum-deprived MC3T3-E1 osteoblasts, mechanical stimulation caused by mild (287 x g) centrifugation induced a 10-fold increase in mRNA levels of the proto-oncogene, c-fos. Induction of c-fos was abolished by the cAMP-dependent protein kinase inhibitor H-89, suggesting that the transient c-fos mRNA increase is mediated by cAMP. Down-regulation of protein kinase C (PKC) activity by chronic TPA treatment failed to significantly reduce c-fos induction, suggesting that TPA-sensitive isoforms of PKC are not responsible for c-fos up-regulation. In addition, 287 x g centrifugation increased intracellular prostaglandin E2 (PGE2) levels 2.8-fold (P<0. 005). Since we have previously shown that prostaglandin E2 (PGE2) can induce c-fos expression via a cAMP-mediated mechanism, we asked whether the increase in c-fos mRNA was due to centrifugation-induced PGE2 release. Pretreatment with the cyclooxygenase inhibitors indomethacin and flurbiprofen did not hinder the early induction of c-fos by mechanical stimulation. We conclude that c-fos expression induced by mild mechanical loading is dependent primarily on cAMP, not PKC, and initial induction of c-fos is not necessarily dependent on the action of newly synthesized PGE2.
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PMID:Mechanically induced c-fos expression is mediated by cAMP in MC3T3-E1 osteoblasts. 1006 22

Cholera toxin (CTX), an activator of G(s) protein, is an important pharmacological tool in G protein research. The effect and the mechanism of action of CTX in the gastrointestinal smooth muscle, including the internal anal sphincter (IAS), are not known. The present investigation was carried out to examine the effects of CTX on the signal transduction associated with the adenylate cyclase (AC) pathway on the basal tone of the IAS smooth muscle. CTX caused a prompt and dose-dependent fall in the basal tone of the IAS that was not affected by the neurotoxins TTX and omega-conotoxin or the nitric oxide synthase inhibitor N(G)-nitro-L-arginine. The cyclooxygenase inhibitor indomethacin, cAMP-dependent protein kinase inhibitor Rp-8-bromoadenosine 3',5' cyclic monophosphorothioate inhibited CTX-induced IAS smooth muscle relaxation. Furthermore, CTX caused a concentration-dependent relaxation of the isolated smooth muscle cells (SMC) of the IAS, which was blocked by G(s)alpha antibody (G(s)alpha-Ab). The IAS smooth muscle relaxation was accompanied with an increase in the GTPase activity that was also specifically blocked by G(s)alpha-Ab. We conclude that a major part of the inhibitory action of CTX in the IAS is via the direct response of the SMC that is linked with G(s) protein to the AC pathway. A part of the inhibitory action of CTX on the smooth muscle occurs via the activation of cyclooxygenase pathway. The relative contribution of such actions of CTX in the smooth muscle in the gastrointestinal motility disturbances following cholera infection remains to be determined.
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PMID:Mechanism of action of cholera toxin on the opossum internal anal sphincter smooth muscle. 1040 62

In addition to its role as a CNS neurotransmitter, glutamate has been shown recently to be an important component of the peripheral inflammation response. We demonstrated previously that the group I metabotropic glutamate receptors (mGluRs) mGlu1 and mGlu5 are expressed in the peripheral terminals of sensory neurons and that activation of group I mGluRs in the skin increases thermal sensitivity. In the present study, we provide evidence suggesting that group I mGluRs increase thermal sensitivity by enhancing vanilloid (capsaicin) receptor function. We show that mGlu5 potentiates capsaicin responses in mouse sensory neurons by the phospholipase C pathway but not by activation of protein kinase C. Rather, the effects are mediated by the metabolism of diacylglycerol and the production of prostaglandins via the cyclooxygenase pathway, leading to activation of the cAMP-dependent protein kinase subsequent to prostanoid receptor activation. Behavioral thermal sensitization in mice induced by intraplantar injection of mGlu1/5 agonists was also blocked by inhibitors of protein kinase A and cyclooxygenase, suggesting that a similar signaling pathway operates in vivo. These results demonstrate a novel signaling pathway in sensory neurons and provide a plausible mechanism for the enhancement of thermal sensitivity that occurs with inflammation and after activation of mGluRs on peripheral sensory neuron terminals.
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PMID:Prostaglandin and protein kinase A-dependent modulation of vanilloid receptor function by metabotropic glutamate receptor 5: potential mechanism for thermal hyperalgesia. 1219 66

Angiotensin (Ang) peptides play a critical role in regulating vascular reactivity and structure. We showed that Ang-(1-7) reduced smooth muscle growth after vascular injury and attenuated the proliferation of vascular smooth muscle cells (VSMCs). This study investigated the molecular mechanisms of the antiproliferative effects of Ang-(1-7) in cultured rat aortic VSMCs. Ang-(1-7) caused a dose-dependent release of prostacyclin from VSMCs, with a maximal release of 277.9+/-25.2% of basal values (P<0.05) by 100 nmol/L Ang-(1-7). The cyclooxygenase inhibitor indomethacin significantly attenuated growth inhibition by Ang-(1-7). In contrast, neither a lipoxygenase inhibitor nor a cytochrome p450 epoxygenase inhibitor prevented the antiproliferative effects of Ang-(1-7). These results suggest that Ang-(1-7) inhibits vascular growth by releasing prostacyclin. Ang-(1-7) caused a dose-dependent release of cAMP, which might result from prostacyclin-mediated activation of adenylate cyclase. The cAMP-dependent protein kinase inhibitor Rp-adenosine-3',5'-cyclic monophosphorothioate attenuated the Ang-(1-7)-mediated inhibition of serum-stimulated thymidine incorporation. Finally, Ang-(1-7) inhibited Ang II stimulation of mitogen-activated protein kinase activities (ERK1/2). Incubation of VSMCs with concentrations of Ang-(1-7) up to 1 micromol/L had no effect on ERK1/2 activation. However, preincubation with increasing concentrations of Ang-(1-7) caused a dose-dependent reduction in Ang II-stimulated ERK1/2 activities. Ang-(1-7) (1 micromol/L) reduced 100 nmol/L Ang II-stimulated ERK1 and ERK2 activation by 42.3+/-6.2% and 41.2+/-4.2%, respectively (P<0.01). These results suggest that Ang-(1-7) inhibits vascular growth through the release of prostacyclin, through the prostacyclin-mediated production of cAMP and activation of cAMP-dependent protein kinase, and by attenuation of mitogen-activated protein kinase activation.
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PMID:Molecular mechanisms of inhibition of vascular growth by angiotensin-(1-7). 1295 14

Prostaglandin E2 (PGE2), a major product of cyclooxygenase, has been implicated in modulating angiogenesis, vascular function, and inflammatory processes, but the underlying mechanism is not clearly elucidated. We here investigated the molecular mechanism by which PGE2 regulates angiogenesis. Treatment of human umbilical vein endothelial cells (HUVEC) with PGE2 increased angiogenesis. PGE2 increased phosphorylation of Akt and endothelial nitric oxide synthase (eNOS), eNOS activity, and nitric oxide (NO) production by the activation of cAMP-dependent protein kinase (PKA) and phosphatidylinositol 3-kinase (PI3K). Dibutyryl cAMP (DB-cAMP) mimicked the role of PGE2 in angiogenesis and the signaling pathway, suggesting that cAMP is a down-stream mediator of PGE2. Furthermore, PGE2 increased endothelial cell sprouting from normal murine aortic segments, but not from eNOS-deficient ones, on Matrigel. The angiogenic effects of PGE2 were inhibited by the inhibitors of PKA, PI3K, eNOS, and soluble guanylate cyclase, but not by phospholipase C inhibitor. These results clearly show that PGE2 increased angiogenesis by activating the NO/cGMP signaling pathway through PKA/PI3K/Akt-dependent increase in eNOS activity.
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PMID:Prostaglandin E2 stimulates angiogenesis by activating the nitric oxide/cGMP pathway in human umbilical vein endothelial cells. 1639 20

The aim of this study was to investigate the mechanisms by which N,N'-dimethylbiguanide metformin (50 mg/100 g body weight (BW) in 0.05 ml of water, given orally with a cannula) prevents the ovarian disorders provoked by the hyperandrogenization with dehydroepiandrosterone (DHEA) in prepuberal BALB/c mice. The injection of DHEA (6 mg/100 g BW in 0.1 ml of oil) for 20 consecutive days re-creates a mouse model that resembles some aspects of the human polycystic ovary syndrome (PCOS). The treatment with DHEA increased ovarian oxidative stress because it enhanced lipid peroxidation (LPO) and diminished both catalase (CAT) activity and glutathione (GSH) content. Therefore, the treatment with DHEA diminished both ovarian nitric oxide synthase (NOS) activity and prostaglandin E (PGE) production. When metformin was administered together with DHEA, the ovarian GSH content, NOS activity and PGE production did not differ when compared with controls. However, metformin was not able to prevent the effect of DHEA on ovarian LPO or CAT activity. Finally, DHEA increased the ovarian protein expressions of inducible NOS (iNOS), inducible cyclooxygenase (COX2) and the phosphorylated AMP-dependent kinase alpha (AMPK-alpha) (Thr172). Metformin administered together with DHEA was able to prevent the increase of ovarian iNOS and COX2 expressions and to enhance the activation of phosphorylated AMPK-alpha expression.
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PMID:The mechanisms involved in the action of metformin in regulating ovarian function in hyperandrogenized mice. 1680 78


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