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)

The aim of our study was to examine the involvement of IGF-II, tyrosine kinases (TK)- and MAP kinases (MAPK)-dependent intracellular mechanisms in the control of ovarian functions in the domestic fowl, as well as the role of these kinases in mediating the IGF-II effect on this process. For this purpose, we studied the influence of IGF-II (0,1,10 or 100 ng/ml), inhibitors of TK (AG1024, 1 microg/ml), MAPK (PD98059, 5 microg/ml), and their combinations, on proliferation (expression of proliferation-related substances PCNA), apoptosis (apoptosis-associated protein bax), TK (phosphotyrosine), MAPK (ERK1,2), cyclin-dependent protein kinase 2 (p34/cdc2) and transcription factor CREB-1, as well as on the release of progesterone (P), testosterone (T), estradiol (E) and arginine-vasotocin (AVT) in cultured fragments of ovarian follicles. The presence of substances within ovarian cells was evaluated by SDS PAGE-Western immunoblotting, and release of the substances was measured by using RIA/EIA of ovarian fragments-conditioned medium. It was found, that the addition of IGF-II to the culture medium (1-100 ng/ml) substantially increased expression of PCNA, MAPK and CREB, and decreased the level of p34/cdc2 and bax, but not TK. Furthermore, exogenous IGF-II inhibited P (at a concentration of 100 ng IGF-II/ml medium), and stimulated T (1,10,100 ng/ml), E (10,100 ng/ml) and AVT (1 ng/ml) release by cultured ovarian cells. Inhibitor of TK, when given alone, increased MAPK and E, inhibited p34/cdc2 and AVT, and did not affect accumulation of TK, P or T. Furthermore, TK blocker prevented effects of IGF-II on T, E and AVT, but not on TK, MAPK, p34/cdc2 and P. MAPK blocker augmented PCNA, MAPK, T and AVT expression, but not P or E, and suppressed expression of p34/cdc2 and bax. Furthermore, MAPK inhibitor, given together with IGF-II, prevented or even reversed the action of IGF-II on PCNA, P, T and AVT, but not on MAPK, p34/cdc2, CREB, bax or E. These observations suggest the involvement of IGF-II, TK and MAPK in the control of proliferation, apoptosis, steroid and peptide hormones by avian ovarian cells, as well as of the involvement of these kinases in mediation of some IGF-II effects on ovarian cells.
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PMID:Role of tyrosine kinase- and MAP kinase-dependent intracellular mechanisms in control of ovarian functions in the domestic fowl (Gallus domesticus) and in mediating effects of IGF-II. 1496 54

Physical forces play an important role in regulating cell functions. We applied mechanical strain to human fibroblasts by magnetic attraction of superparamagnetic arginine-glycine-aspartic acid (RGD)-coated beads. We confirmed that the MAP kinases Erk and p38 are activated by mechanical strain, and went further by demonstrating the activation of Elk-1 by mechanical strain, mainly through a MEK-Erk pathway. Transfection of a dominant negative form of the G protein rac-1 (rac T17N), and inhibition of PI3K, an effector of rac-1, efficiently prevented Elk-1 activation by mechanical forces. Transfection with C3 transferase, known to inhibit rhoA, and inhibition of rock (a downstream effector of rhoA), gave similar results. However, contrary to the active form of rhoA (rho G14V), transfection of the active form of rac-1 (rac G12V) induced Elk activation and mimicked the effects of mechanical strain. These results point out that the two small G proteins rhoA and rac-1 participate in cell sensitivity to mechanical strain and lead to the modulation of the Erk pathway.
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PMID:ERK activation by mechanical strain is regulated by the small G proteins rac-1 and rhoA. 1500 99

The neoplastic production of the insulin-like growth factor binding protein (IGFBP)-2 often correlates with tumor malignancy and aggressiveness. Since IGFBP-2 contains an RGD motif in its C-terminus, it was hypothesized that this protein may act independently of IGF on tumor cells through integrins. To investigate this, integrin binding, intracellular signaling and the impact of IGFBP-2 on cell adhesion and proliferation were examined in two tumor cell lines. In tracer displacement studies, up to 30% of the added (125)I-hIGFBP-2 specifically bound to the cells. Bound (125)I-hIGFBP-2 was reversibly displaced by IGFBP-2, IGFBP-1 and RGD-(Gly-Arg-Asp)-containing peptides, but not by IGFBP-3, -4, -5, -6 and RGE-(Gly-Arg-Glu)-containing peptides. Blocking with antibodies directed against different integrins and with fibronectin demonstrated that IGFBP-2 cell surface binding is specific for alpha5beta1-integrin. Incubation of IGFBP-2 with equimolar quantities of IGF-I and IGF-II annihilated RGD-specific binding. IGFBP-2 binding at the cell surface led to dephosphorylation of the focal adhesion-kinase (FAK) of up to 37% (P<0.01), and of the p42/44 MAP-kinases of up to 40% (P<0.01). In addition, IGFBP-2 promoted de-adhesion of the cells dose-dependently by up to 30% (P<0.05), and reduced proliferation by 24% (P<0.01). Since one of the cell lines used does not express a functional IGF-I receptor, these data demonstrate that IGFBP-2 can act in an IGF-independent manner, at least in part by an interaction with alpha5beta1-integrin.
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PMID:Integrin-mediated action of insulin-like growth factor binding protein-2 in tumor cells. 1517 17

In human saphenous vein endothelial cells (HSVECs), tumor necrosis factor-alpha (TNFalpha) and bacterial lipopolysaccharide (LPS), but neither interferon gamma (IFNgamma) nor interleukin 1beta (IL-1beta), stimulate arginine transport. The effects of TNFalpha and LPS are due solely to the enhancement of system y+ activity, whereas system y+L is substantially unaffected. TNFalpha causes an increased expression of SLC7A2/CAT-2B gene while SLC7A1/CAT-1 expression is not altered by the cytokine. The suppression of PKC-dependent transduction pathways, obtained with the inhibitor chelerytrhine, the inhibitor peptide of PKCzeta isoform, or chronic exposure to phorbol esters, does not prevent TNFalpha effect on arginine transport. Likewise, ERK, JNK, and p38 MAP kinases are not involved in the cytokine effect, since arginine transport stimulation is unaffected by their specific inhibitors. On the contrary, inhibitors of NF-kappaB pathway hinder the increase in CAT2B mRNA and the stimulation of arginine uptake. These results indicate that in human endothelial cells the activation of NF-kappaB pathway mediates the TNFalpha effects on arginine transport.
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PMID:The stimulation of arginine transport by TNFalpha in human endothelial cells depends on NF-kappaB activation. 1523 57

We hypothesized that the effective inhibition of nitric oxide synthase (NOS), achieved via systemic infusion of N(G)-nitro-l-arginine methyl ester (l-NAME), would reduce the gas exchange threshold (GET) and the maximal oxygen uptake (V(.)(O(2)max)) during incremental cycle exercise in man if NO is important in the regulation of muscle vasodilatation. Seven healthy males, aged 18-34 years, volunteered to participate in this ethically approved study. On two occasions, the subjects completed an incremental exercise test to exhaustion on an electrically braked cycle ergometer following the infusion of either l-NAME (4 mg kg(-1) in 50 ml saline) or placebo (50 ml saline, CON). At rest, the infusion of l-NAME resulted in a significant increase in mean arterial pressure (MAP; CON vs. l-NAME, 89 +/- 8 vs. 103 +/- 11 mmHg (mean +/- s.d.; P < 0.05)) and a significant reduction in heart rate (HR; CON vs. l-NAME, 60 +/- 12 vs. 51 +/- 8 beats min(-1); P < 0.01). At submaximal work rates, there was no significant difference in V(.)(O(2)) between the conditions and no difference in the GET (CON vs. l-NAME, 1.94 +/- 0.47 vs. 2.01 +/- 0.41 l min(-1)). However, at higher work rates, differences in V(.)(O(2)) between the conditions became more pronounced such that V(.)(O(2)max) was significantly lower with l-NAME (CON vs. l-NAME, 4.02 +/- 0.41 vs. 3.80 +/- 0.34 l min(-1); P < 0.05). The reduction in V(.)(O(2)max) was associated with a reduction in HR(max) (CON vs. l-NAME, 186 +/- 10 vs. 178 +/- 7 beats min(-1); P < 0.01). These results demonstrate that NOS inhibition with l-NAME has no effect on GET but reduces V(.)(O(2)max) during large muscle group exercise in man, presumably by direct or indirect effects on cardiac output and muscle blood flow.
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PMID:Nitric oxide synthase inhibition with L-NAME reduces maximal oxygen uptake but not gas exchange threshold during incremental cycle exercise in man. 1528 44

This study was designed to determine if the thyroid hormone analog 3,5 diiodothyropropionic acid (DITPA), now in clinical trials for heart failure, alters endothelial function after myocardial infarction (MI). Three weeks after MI, adult Sprague-Dawley rats were randomly assigned to DITPA (375 microg/100 g subcutaneous) or no treatment of 3 weeks. In MI rats, left ventricular (LV) end-diastolic pressure and LV dP/dt decreased (P < 0.05). DITPA did not change MAP (87 +/- 10 versus 90 +/- 7 mm Hg) or LV end-diastolic pressure (23 +/- 3 versus 19 +/- 9 mm Hg) but did lower (P < 0.05) LV dP/dt (4,633 +/- 797 versus 3,650 +/- 1,236 mm Hg/s). In aortic segments from MI rats, DITPA enhanced the acetylcholine dependent vasorelaxation (59 +/- 11% at 10(-4) M, P < 0.05) and isoproterenol induced vasorelaxation (57 +/- 13% at 10(-4) M, P < 0.05). The increases in vasorelaxation were blocked with l-NAME and restored with L-arginine. Treatment with DITPA increased (P < 0.05) eNOS protein content in aortic tissue from sham rats (3.8 +/- 2.8 to 44.5 +/- 7.1 integrated intensity units (II)/microg) and in MI rats (5.3 +/- 3.4 to 28.3 +/- 8.9 II/microg). In endothelial cells, 24 hours' treatment with DITPA (10 microM) increased (P < 0.01) eNOS protein expression from 22.1 +/- 4.8 to 52.7 +/- 16.8 II/microg protein and DITPA (20 microM) increased eNOS to 49.1+/- 15.2 II/microg protein. The thyroid analog DITPA enhances endothelial nitric oxide and beta-adrenergic-mediated vasorelaxation by increasing nitric oxide in the vasculature.
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PMID:Thyroid hormone analog, DITPA, improves endothelial nitric oxide and beta-adrenergic mediated vasorelaxation after myocardial infarction. 1545 53

Hemorrhagic shock stimulates nitric oxide (NO) biosynthesis through upregulation of inducible NO synthase (iNOS) expression. Trans-membrane l-arginine transportation mediated by the isozymes of cationic amino acid transporters (e.g. CAT-1, CAT-2, CAT-2A, and CAT-2B) is one crucial regulatory mechanism that regulates iNOS activity. We sought to assess the effects of hemorrhage and resuscitation on the expression of these regulatory enzymes in hemorrhage-stimulated rat lungs. Twenty-four rats were randomized to a sham-instrumented group, a sustained shock group, a shock with blood resuscitation group, or a shock with normal saline resuscitation group. Hemorrhagic shock was induced by withdrawing blood to maintain MAP between 40 and 45mmHg for 60min. Resuscitation by infusing blood/saline mixtures (blood resuscitation group) or saline alone (saline resuscitation group) was then performed. At the end of the experiment (300min after hemorrhage began), rats were sacrificed and enzymes expression as well as pulmonary NO biosynthesis and lung injuries were assayed. Our data revealed that hemorrhage-induced pulmonary iNOS, CAT-2, and CAT-2B transcription which was associated with pulmonary NO overproduction and subsequent lung injury. Resuscitation significantly attenuated the hemorrhage-induced enzyme upregulation, pulmonary NO overproduction, and lung injury. Blood/saline mixtures were superior to saline as a resuscitation solution in treating hemorrhage-induced pulmonary NO overproduction and lung injury. Hemorrhage and/or resuscitation, however, did not affect the expression of pulmonary CAT-1 and CAT-2A. It is, therefore, concluded that the expression of pulmonary iNOS, CAT-2, and CAT-2B is inducible and that of CAT-1 and CAT-2A is constitutive in hemorrhagic shock rat lungs.
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PMID:Pulmonary transcription of CAT-2 and CAT-2B but not CAT-1 and CAT-2A were upregulated in hemorrhagic shock rats. 1553 Oct 73

Cigarette-induced endothelial dysfunction could be an early mediator of atherosclerosis. In this study, we explored the mechanisms of cigarette smoke extract (CSE)-induced human aortic endothelial cells (HAEC) apoptosis. We found that 10-65% of HAECs underwent apoptotic changes when HAECs were exposed to 0.001-0.02 cigarette equivalent unit of CSE for 4 h. CSE activated the caspases-3 and 8, the p38 MAP kinase and stress activated protein kinase/c-Jun N-terminal protein kinase (SAPK/JNK). Specific inhibitors of p38 MAP or SAPK/JNK reduced CSE-induced caspase activation. We further showed that eNOS pre-activation by L-arginine reduced endothelial apoptosis from 65% to 5%; and eNOS inhibition by N-omega-nitro-L-arginine methyl ester accentuated CSE-induced endothelial apoptosis. We suggest that appropriate endogenous NO production may be an important protective mechanism against smoking-induced endothelial damage.
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PMID:Endogenous nitric oxide activation protects against cigarette smoking induced apoptosis in endothelial cells. 1567 Aug 37

The crystal structure of the methionine aminopeptidase (MetAP) from Mycobacterium tuberculosis (MtMetAP1c) has been determined in the apo- and methionine-bound forms. This is the first structure of a type I MetAP with a significant extension at the amino terminus. The catalytic domain is similar to that of Escherichia coli MetAP (EcMetAP), and the additional 40-residue segment wraps around the surface with an extended but well-defined structure. There are several members of the actinomyces family of bacteria that contain MetAPs with such N-terminal extensions, and we classify these as MetAP type Ic (MetAP1c). Some members of this family of bacteria also contain a second MetAP (type Ia) similar in size to EcMetAP. The main difference between the apo- and the methionine-bound forms of MtMetAP1c is in the conformation of the metal-binding residues. The position of the methionine bound in the active site is very similar to that found in many of the known members of this family. Side chains of several residues in the S1 and S1' subsites shift as much as 1.5 A compared to EcMetAP. Residues 14-17 have the sequence Pro-Thr-Arg-Pro and adopt the conformation of a polyproline II helix. Model-building suggests that this PxxP segment can bind to an SH3 protein motif. Other type Ib and type Ic MetAPs with N-terminal extensions contain similarly located PxxP motifs. Also, several ribosomal proteins are known to include SH3 domains, one of which is located close to the tunnel from which the nascent polypeptide chain exits the ribosome. Therefore, it is proposed that the binding of MetAPs to the ribosome is mediated by a complex between a PxxP motif on the protein and an SH3 domain on the ribosome. It is also possible that zinc-finger domains, which are located at the extreme N-terminus of type I MetAPs, may participate in interactions with the ribosome.
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PMID:Identification of an SH3-binding motif in a new class of methionine aminopeptidases from Mycobacterium tuberculosis suggests a mode of interaction with the ribosome. 1588 55

Beta-endorphin decreases blood pressure in normal rats but increases blood pressure in obese rats. Since beta-endorphins can bind both mu opioid and kappa-opioid receptors we investigated the effect of a mu specific receptor agonist, D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) and a mu specific antagonist, D-Phe-Cys-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) on cardiovascular responses in conscious control and obese rats. Rats were also implanted with telemetry transmitters and intracerebroventricular (ICV) cannulas for recording and peptide administration. The mu agonist, DAMGO, increased blood pressure (BP) in control rats. DAMGO also increased BP in obese rats but only at high concentrations. The heart rate responses paralleled the MAP responses. CTAP, the mu antagonist, paradoxically increased the MAP in both control and obese rats. The responsiveness to the mu agonist and antagonist was greater in controls. In other animals the brains were excised and the ventral medial hypothalamic area removed and mu receptor expression determined using PCR. The expression of mu opioid receptors was increased in obese rats. We conclude that the mu opioids can stimulate cardiovascular responses, but the excitatory responsiveness was not increased in conscious obese rats.
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PMID:The cardiovascular responses to mu opioid agonist and antagonist in conscious normal and obese rats. 1629 44


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