Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genistein, an inhibitor of protein tyrosine kinase (PTK), enhanced the activation of the cardiac isoform of the protein kinase A (PKA)-regulated cystic fibrosis transmembrane conductance regulator (CFTR) Cl- conductance in guinea-pig ventricular cells. We examined the mechanism(s) underlying this excitatory action of genistein by using patch-clamp techniques. The CFTR Cl- conductance, activated by isoproterenol (ISO, 10 nM; [Cl-] 153 mM extracellular, 21 mM intracellular; 36 degrees C), was enhanced by 20 microM genistein. Daidzein, a structural analogue of genistein with little inhibitory action on PTK, also enhanced CFTR Cl- currents. After maximal activation of the Cl- conductance by a cocktail of adenosine 3', 5'-cyclic monophosphate, 3-isobutyl-1-methylxanthine and okadaic acid or vanadate plus forskolin in the pipette, genistein was no longer stimulatory but was rather slightly inhibitory at 100 microM. Direct exposure of myocytes to higher concentrations of genistein (50-100 microM) elicited outwardly rectifying currents with a reversal potential of -47 mV in the absence of ISO. In the presence of 50 microM H-89, a PKA inhibitor, genistein had no effect. Vanadate in the pipette at a concentration (100 microM) inhibiting phosphotyrosine phosphatases alone did not prevent the action of genistein. In contrast, no conductance was activated by tyrphostins B42 or 51 or lavendustin A, other PTK inhibitors. Genistein's stimulation of cardiac CFTR Cl- conductance appears to be independent of the PTK pathway and to be due to its direct interaction with CFTR Cl- channels.
...
PMID:On the mechanism of genistein-induced activation of protein kinase A-dependent Cl- conductance in cardiac myocytes. 1039 55

In renal proximal tubules, the basolateral organic anion [p-aminohippurate (PAH)] transporter is functionally coupled to the sodium-dependent dicarboxylate transporter. This study was undertaken to elucidate whether protein kinases differentially modulate the activities of these transporters. In isolated S(2) segments of proximal tubules microdissected from rabbit kidneys, we investigated whether the transporters are regulated by tyrosine kinases, phosphatidylinositol 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK). The tubules were collapsed; hence, tubular uptake of the marker substances [(3)H]PAH and [(14)C]glutarate reflects transport across the basolateral cell membrane. Genistein, a selective inhibitor of tyrosine kinase, diminished PAH uptake at 10(-7) M by 15.6 +/- 11.7% and at 10(-6) M by 25.6 +/- 9.1%. An inactive analog of genistein, diadzein, was without effect even at a concentration 100-fold higher than the lowest concentration of genistein, which produced significant reduction of PAH uptake. At 10(-7) M, wortmannin, a selective inhibitor of PI3K, reduced PAH uptake by 24.1 +/- 11.3% and, at 10(-6) M, it reduced it by 32.9 +/- 11.8%. The selective inhibitor of MAPK, PD98059, diminished PAH uptake at 5 x 10(-5) M by 23.2 +/- 6.8% and at 10(-4) M by 18.3 +/- 5.2%. Glutarate uptake was not reduced by any of these protein kinase inhibitors. Insulin had no effect on PAH uptake. These findings indicate that, in addition to protein kinase A, protein kinase C and calcium/calmodulin-dependent protein kinase II (former studies from this laboratory), as well as tyrosine kinases, PI3K, and MAPK, modulate renal basolateral PAH transport, whereas none of these protein kinases affects basolateral glutarate transport. Thus, the results provide evidence for differential regulation of basolateral transporters for PAH and dicarboxylates.
...
PMID:Evidence for differential regulation of renal proximal tubular p-aminohippurate and sodium-dependent dicarboxylate transport. 1041 82

IFN-gamma-inducible protein-10 (IP-10) is a chemokine, which plays an important role in mediating inflammation by attracting activated T cells, and it has been demonstrated in inflammatory skin diseases and cutaneous T cell lymphomas. Keratinocytes can abundantly produce IP-10 mRNA after IFN-gamma treatment. In this study we explored possibilities to downregulate IP-10 expression using human cultured keratinocytes as a model system. Decreased IP-10 mRNA levels were found using specific inhibitors of protein kinase (PK)-C (H-7 and Calphostin C). Moreover, depletion of PK-C by pretreatment of the cells with phorbol myristate (PMA) also down-regulated IP-10 mRNA expression. In addition, elevated cAMP levels were shown to inhibit IP-10 mRNA expression as could be concluded from experiments with forskolin and W-7, substances which, directly or indirectly, raise the intracellular cAMP level. With Genistein, an inhibitor of tyrosine kinase, the IFN-gamma-induced IP-10 mRNA expression was also found to be diminished. These data suggest that inhibitors of the IP-10 mRNA expression in cultured keratinocytes may be potentially of clinical relevance to suppress inflammatory processes in the skin.
...
PMID:IP-10 mRNA expression in cultured keratinocytes is suppressed by inhibition of protein kinase-C and tyrosine kinase and elevation of cAMP. 1041 47

By using tissue miniunits, protein kinase modulators, and topoisomerase inhibitors in short-term incubation (0-90 min) we studied (1) the role of protein phosphorylation in the immediate control of DNA replication in the developing rat cerebral cortex and (2) the mechanism of action for genistein-mediated DNA synthesis inhibition. Genistein decreased the DNA synthesis within less than 30 min. None of the other protein kinase inhibitors examined (herbimycin A, staurosporine, calphostin-C) or the protein phosphatase inhibitor sodium orthovanadate inhibited DNA synthesis and they did not affect the genistein-mediated inhibition. The selective topoisomerase inhibitors camptothecin and etoposide decreased the DNA synthesis to an extent similar to that of genistein and within less than 30 min. In addition, the effects of these substances on topoisomerase I and II were studied. Etoposide and genistein but not herbimycin A, staurosporine, or calphostin-C strongly inhibited the activity of topoisomerase II. Our results (1) strongly suggest that the net rate of DNA replication during the S phase of the cell cycle is independent of protein phosphorylation and (2) indicate that the early inhibitory effect of genistein on DNA synthesis is mediated by topoisomerase II inhibition rather than protein tyrosine kinase inhibition.
...
PMID:Early effects of protein kinase modulators on DNA synthesis in rat cerebral cortex. 1048 85

Bile-salt-dependent lipase (BSDL, EC 3.1.1.-) is an enzyme expressed by the pancreatic acinar cells and secreted as a component of the pancreatic juice of all examined species. During its secretion route BSDL is associated with intracellular membranes. This association allows the complete glycosylation of the enzyme or participates in the inhibition of the enzyme activity, which can deleterious for the acinar pancreatic cell. Thereafter, the human BSDL is phosphorylated by a serine/threonine protein kinase and released from intracellular membranes. In the present study, we show that the rat pancreatic BSDL, expressed by AR4-2J cells used as a model, is phosphorylated by a protein kinase that is insensitive to inhibitors of protein kinases A, C or G and that the phosphorylation process is favoured by okadaic acid (an inhibitor of protein phosphatases 1 and 2A). However, 5,6-dichloro-1-beta-d-ribofuranosylbenzimidazole (DRB), which is a specific inhibitor of casein kinase II, abolishes the phosphorylation in vitro of BSDL within micro- somes of AR4-2J pancreatic cells. We showed further that the alpha-subunit of casein kinase II co-locates with BSDL within the lumenal compartment of the Golgi. Genistein, which perturbs the trans-Golgi network, also inhibits the phosphorylation of BSDL, suggesting that this post-translational modification of BSDL probably occurred within this cell compartment. The inhibition of the phosphorylation of BSDL by DRB also decreases the rate at which the enzyme is secreted. Under the same conditions, the rate of alpha-amylase secretion was not modified. These data strongly suggest that phosphorylation is a post-translational event, which appears to be essential for the secretion of BSDL.
...
PMID:Phosphorylation of the rat pancreatic bile-salt-dependent lipase by casein kinase II is essential for secretion. 1060 Jun 47

The effect of genistein on anion secretion via cystic fibrosis transmembrane conductance regulator (CFTR) in cultured rat cauda epididymal epithelia was studied by short-circuit current (Isc) technique. Genistein added apically stimulated a concentration-dependent rise in Isc due to Cl(-) and HCO(3)(-) secretion. The genistein-induced Isc was observed in basolaterally permeabilized monolayers, suggesting that the Isc response was mediated by the apical anion channel. The response could be blocked by the nonspecific Cl(-) channel blocker, diphenylamine-2-carboxylate (DPC), but not by the Ca(2+)-activated Cl(-) channel blocker, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS). Genistein did not increase intracellular cAMP, but H-89, a protein kinase A inhibitor, completely abolished the Isc response to genistein. Moreover, pretreatment of the tissues with MDL-12330A, an adenylate cyclase inhibitor, markedly attenuated the Isc response to genistein, but the response was restored upon the addition of exogenous cAMP. Ca(2+), protein kinase C, tyrosine kinase, and protein phosphatase signalling pathways were not involved in the action of genistein. It is speculated that genistein stimulates anion secretion by direct interaction with CFTR. This requires a low level of phosphorylation of CFTR by basal protein kinase A activity. It is suggested that genistein may provide therapeutic benefit to male infertility associated with cystic fibrosis.
...
PMID:Activation of cystic fibrosis transmembrane conductance regulator in rat epididymal epithelium by genistein. 1061 Oct 78

The aim of the present study was to investigate the mechanisms that regulate the activation of phospholipase D (PLD) by endothelin (ET)-1 in rat myometrium. We previously reported that ET-1 exerted part ( approximately 50%) of its effect via protein kinase C (PKC) activation. We now show that in addition to ET-1 and 4beta-phorbol-12,13-dibutyrate (PDBu), pervanadate also stimulated PLD activity. Stimulation by pervanadate was not affected by the PKC inhibitor Ro-31-8220 but was abolished by protein tyrosine kinase (PTK) inhibitors genistein and tyrphostin-47. Genistein partially reduced (52%) ET-1 stimulation, which was further attenuated (96%) by Ro-31-8220, indicating that PTKs may account for the PKC-independent arm of ET-1-stimulated PLD activity. Cell-permeable ceramides reduced ( approximately 50%) the activation of PLD by ET-1 and PDBu but not that by pervanadate. Inhibition was also achieved by sphingomyelinase but not with sphingosine. Inhibition by genistein and D-erythro-N-hexanoyl-sphingosine was additive, whereas inhibition by Ro-31-8220 and D-erythro-N-hexanoyl-sphingosine was not, indicating that ceramide affected the PKC-dependent process involved in PLD activation by ET-1. Forskolin, as well as dibutyryl-cAMP and iloprost, attenuated (approximately 50%) the activation of PLD by ET-1 and pervanadate but not that by PDBu. Inhibition by forskolin was prevented by H-89, an inhibitor of protein kinase A. Inhibition by forskolin and ceramide was additive, whereas inhibition by genistein and forskolin was not, indicating that the cAMP/protein kinase A cascade affected the PTK-dependent process involved in PLD activation by ET-1. The data illustrate a cross-talk between separate signaling pathways, resulting in positive and negative regulation of PLD in rat myometrium.
...
PMID:The roles of protein kinase C and tyrosine kinases in mediating endothelin-1-stimulated phospholipase D activity in rat myometrium: differential inhibition by ceramides and cyclic AMP. 1064 Mar

It is well known that psoriasis, an immunogenetic cutaneous disorder whose major pathogenic findings are epidermal hyperplasia and T-cell infiltration, is aggravated by psychological stresses. Although the exact mechanism is not yet clarified, antidromic secretion of neuropeptides by cutaneous nerve fibers is thought to be involved. In this study, we examined the effect and mechanism of vasoactive intestinal polypeptide (VIP), one of the major neuropeptides, on the proliferation of HaCaT cell which is a spontaneous, immortalized, human keratinocyte cell line. Twenty-four and 48 h after its addition, 1 pM to 100 nM of VIP increased the number of cells cultured with/without serum. We indirectly verified VIP(1)R on the surface of HaCaT cell based on the proliferative ability of various VIP families such as VIP, PACAP and secretin, and increased PKA level 30 min after stimulation. However, because H-89, a PKA inhibitor, did not inhibit the proliferative potential of VIP, its mitogenicity is not medicated through VIP(1)R. One nM VIP produced the TGF-alpha protein which is a strong mitogen of keratinocytes and increased in the psoriatic lesion 2.25 times more compared with the control. Genistein, a tyrosine kinase inhibitor, abrogated the mitogenic activity of VIP. Like VIP, VIP fragments, VIP(1-12) and VIP(10-28) also acted as a mitogen for HaCaT cells through the same mechanism. Collectively, our studies clearly show that VIP and its fragments stimulate keratinocyte growth, not through increased cAMP level, but through increased TGF-alpha protein production.
...
PMID:Vasoactive intestinal polypeptide stimulates the proliferation of HaCaT cell via TGF-alpha. 1065 22

Polychlorinated biphenyls (PCBs) activate neutrophils to induce degranulation and undergo superoxide production through a mechanism that involves stimulation of phospholipase A(2) (PLA(2)). Since the biochemical processes leading to the PCB-induced activation of this enzyme are unknown, the objective of this study was to determine whether protein phosphorylation has a role in this mechanism. Isolated rat neutrophils were labeled with [(3)H]-arachidonic acid ([(3)H]-AA), and activation of PLA(2) was determined from release of radioactivity into the medium. Exposure to the PCB mixture Aroclor 1242 induced release of [(3)H]-AA, and pretreatment with bromoenol lactone (BEL), an inhibitor of calcium-independent PLA(2), diminished release by 80%. Genistein, an inhibitor of tyrosine kinases, caused a small but significant decrease in Aroclor 1242-stimulated release of [(3)H]-AA. Daidzein, a genistein analog with no activity to inhibit tyrosine kinases, had no effect on [(3)H]-AA release. An inhibitor of p38 mitogen-activated protein kinase (MAPK), SB203580, did not affect Aroclor 1242-induced PLA(2) activity at concentrations selective for p38 MAPK; however, PD 98059, which inhibits MAPK kinase (MEK), decreased [(3)H]-AA release to about the same extent as genistein. Treatment of neutrophils with Aroclor 1242 induced phosphorylation of p44 MAPK, and this phosphorylation was unaffected by BEL but was inhibited by PD 98059. Staurosporine, a nonselective inhibitor of protein kinase C (PKC), inhibited PCB-induced release of [(3)H]-AA. Ro 32-0432, a selective inhibitor of PKC(alpha) and PKC(beta1), produced the greatest degree of inhibition (40%) among the tested protein kinase inhibitors. These results suggest that tyrosine kinases, PKC, and the MEK/MAPK pathway are involved in a fraction of Aroclor 1242-induced activation of PLA(2).
...
PMID:Role of protein phosphorylation in activation of phospholipase A2 by the polychlorinated biphenyl mixture Aroclor 1242. 1066

Fucoid algae, including the genus Fucus and Pelvetia, are recognized as model systems to study early embryogenesis in plants. In particular the zygotes of these fucoid algae are highly suitable experimental systems for investigating the establishment of polarity and its requirement for later embryogenesis. However, the transduction pathways involved in the initiation of polarization are still poorly understood, and the link between the early polarization processes and embryo long-term patterning has never been experimentally demonstrated. We, therefore, have investigated the putative role of protein phosphorylation in the regulation of early embryogenesis, using a combined pharmacological and biochemical approach. Among the various protein kinase inhibitors tested, a subset of well-known PTK inhibitors, including genistein, prevented germination but had no effect on growth of germinated zygotes and embryos. Inhibition of germination appeared to be a direct consequence of prevention of polarization since genistein and other PTK inhibitors specifically inhibited axis formation in a light-independent manner. Genistein inhibited cellular events associated with polarization such as polarized secretion of cell wall sulfated compounds. Anchorage of F-actin at the rhizoid pole was also inhibited and F-actin redistributed in response to a new light vector. Zygotes inhibited in the polarization process over the period of axis formation recovered from the treatment and displayed differentiated cellular structures after a few days. However, they exhibited a deeply disorganized pattern, suggesting that the early polarization process is essential for normal patterning of the embryo. Western blot analysis of protein phosphorylation showed that the patterns of protein phosphorylation changed during development and were disturbed by treatments with genistein. This drug also inhibited in vitro autophosphorylation. The nature of the genistein-sensitive kinases required for polarization and long-term patterning is discussed in light of these data.
...
PMID:Inhibition of the establishment of zygotic polarity by protein tyrosine kinase inhibitors leads to an alteration of embryo pattern in Fucus. 1069 14


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---