Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of renal mesangial cells with the vasoconstrictor angiotensin II stimulates a concentration-dependent increase in stress-activated protein kinase (SAPK) activity as measured by phosphorylation of the substrate c-Jun. Time course studies reveal a transient SAPK activation by angiotensin II which is maximal after 5-10 min of stimulation and rapidly declines thereafter to basal levels within 30 min. Using the highly selective angiotensin II AT1 receptor antagonist valsartan, a concentration-dependent inhibition of angiotensin II-induced SAPK activity is observed, clearly implying the AT1-receptor in this angiotensin II-mediated response. To further elucidate the mechanism involved in angiotensin II-induced SAPK activation, cells were treated with different inhibitors. Genistein, a tyrosine kinase inhibitor, greatly blocks (by 90%) the angiotensin II response, whereas pertussis toxin only partially inhibits angiotensin II-activated SAPK activity (by 76%). A highly potent protein kinase C inhibitor [3-[1-[3-(amidinothio)propyl-1H-indoyl-3-yl]-3-(1-methyl-1H- indoyl-3-yl) maleimide methane sulfonate], Ro 31-8220, as well as protein kinase C depletion from the cells by prolonged phorbol ester pretreatment, fail to inhibit the angiotensin II-induced SAPK activation. In summary these results suggest that angiotensin II AT1-receptor is able to activate the SAPK cascade in mesangial cells by a pathway independent of protein kinase C, but requiring both pertussis-toxin-sensitive and -insensitive G-proteins and tyrosine kinase activation.
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PMID:Angiotensin II stimulation of the stress-activated protein kinases in renal mesangial cells is mediated by the angiotensin AT1 receptor subtype. 957 Apr 79

Urokinase-type plasminogen activator (uPA) is a key serine protease involved in invasion and metastasis. We had shown that overproduction of uPA in tumor cells is controlled by a phospholipase D-protein kinase C-dependent pathway. Now we studied whether other signaling pathways participate in the regulation of constitutive uPA and metalloproteinase (MMP) overproduction in tumor cells. Staurosporine, a protein kinase inhibitor, stimulated uPA and MMP-9 secretion as measured by radial caseinolysis, zymography and Western blotting. Genistein, a specific tyrosine kinase inhibitor, reduced the constitutive and staurosporine-induced uPA and MMP-9 secretion. Interestingly, the phosphatase inhibitor vanadate stimulated uPA secretion. Verapamil, a calcium channel blocker, inhibited both endogenous and PMA-stimulated secretion of uPA but was unable to inhibit staurosporine-induced secretion. The alcohol n-butanol, a phospholipase D and protein kinase C inhibitor, besides inhibiting constitutive uPA secretion, blocked staurosporine-induced secretion. Our results suggest that constitutive and staurosporine-induced uPA and MMP-9 secretion by LM3 murine mammary tumor cells is controlled by an endogenous tyrosine kinase pathway and probably involves protein phosphatases. In addition, the staurosporine-induced signal regulating urokinase secretion is independent of extracellular calcium but dependent on phospholipase D.
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PMID:Secretion of urokinase and metalloproteinase-9 induced by staurosporine is dependent on a tyrosine kinase pathway in mammary tumor cells. 957 73

Myotrophin, a novel protein that has been shown to stimulate myocyte growth, has been isolated, purified, and sequenced from the hearts of spontaneously hypertensive rats and dilated cardiomyopathic human tissue. Recently, the cDNA clones encoding myotrophin have been isolated and expressed in Escherichia coli, and the recombinant myotrophin was found to be as biologically and immunologically active as natural myotrophin. The mechanism by which myotrophin stimulates protein synthesis and initiates myocardial hypertrophy is not known. To evaluate the involvement of protein kinase C (PKC) in myotrophin-induced hypertrophy, PKC activity and its distribution in the subcellular fraction were determined in cultured neonatal and adult myocytes. PKC activity was determined by measuring the incorporation of 32P into histone type III-S and PKCepsilon substrate peptide (epsilon(pep)) from [gamma-32P]ATP in neonatal myocytes. Myotrophin significantly stimulated PKC activity in neonatal myocytes and was associated with a significant increase in protein synthesis. The effect of myotrophin on the stimulation of PKC activity and [3H]leucine incorporation was abolished by pretreatment with either staurosporine or H-7, two selective, pharmacological PKC inhibitors. Pretreatment of myocytes with staurosporine also reduced the myotrophin-induced mRNA levels of c-fos and beta-myosin heavy chain. To evaluate the subcellular events whose occurrence was due to myotrophin and translocation of PKC, we studied the effect of genistein, a tyrosine kinase inhibitor, on myotrophin-induced neonatal myocyte growth. Genistein attenuated the [3H]leucine incorporation induced by myotrophin. To define the specificity of the PKC isoform(s) involved in myotrophin-stimulated myocyte growth, both neonatal and adult myocytes were treated with myotrophin, and Western blot analyses were performed by using the antibodies of different PKC isoforms. Results showed that both PKCalpha and PKCepsilon isoforms participated in the myotrophin-induced neonatal myocyte growth, whereas only the PKCepsilon isoform was involved in myotrophin-induced adult myocyte hypertrophy. PKCdelta and PKCzeta do not seem to participate in either neonatal or adult myocyte growth induced by myotrophin. Treatment with antisense oligonucleotides specific for PKCalpha and PKCepsilon isoforms further supported this result. PKCalpha is the major PKC isoform in neonatal myocytes and needs Ca2+ and phospholipids for its activation, and PKCepsilon (the Ca2+-independent PKC isoform) is present in both neonatal and adult myocytes; the 15-mer antisense oligodeoxynucleotides of each were used for this study. Treatment of neonatal myocytes with the PKCalpha and PKCepsilon antisense oligodeoxynucleotides for 5 days significantly reduced Ca2+-dependent and Ca2+-independent PKC activity, respectively, as well as the [3H]leucine incorporation induced by myotrophin. Furthermore, myotrophin-induced PKC activity was primarily located in the particulate fraction and did not result in a concomitant decrease in the cytosolic fraction. Myotrophin does not change PKC isoform expression (both Ca2+ dependent and independent PKC isoforms used in this study) in rat neonatal cardiac fibroblasts. Our data suggest that myotrophin exerts its action on protein synthesis, possibly through a tyrosine kinase-coupled pathway and translocation of PKC from the cytosol to the cell membrane.
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PMID:Increased protein kinase C activity in myotrophin-induced myocyte growth. 963 17

Prior studies demonstrated that rat macrophages express CD8, which differs from T lymphocyte CD8 within the ligand binding domain. We investigated whether stimulation of macrophage CD8 could induce mediator release and regulate host defense. Cross-linking either CD8alpha (OX8, 5 microg/ml) or CD8beta (341, 10 microg/ml) stimulated nitric oxide (NO) production, which correlated with an up-regulation of inducible NO synthase protein. Cell signaling inhibitors were used to elucidate the pathways of CD8alpha and CD8beta stimulation. Genistein (broad spectrum protein tyrosine kinase inhibitor, 10 microg/ml), PP1 (src family kinase inhibitor, 5 microg/ml), polymyxin B (protein kinase C (PKC) inhibitor, 100 microg/ml), and Ro 31-8220 (PKC inhibitor, 1 microM) significantly inhibited anti-CD8alpha- and anti-CD8beta-stimulated NO production and inducible NO synthase up-regulation, suggesting that tyrosine kinase(s) (src family) and PKC are involved in CD8 signaling. In addition, cross-linking CD8alpha stimulated NO-dependent macrophage killing of the parasite Leishmania major. For the first time, this work demonstrates that the beta-chain of macrophage CD8, in addition to the alpha-chain, can regulate mediator release. These results further illustrate the importance of this molecule and support our previous data demonstrating differences between macrophage and T lymphocyte CD8. Additional studies on the signaling mechanisms and possible ligand(s) for macrophage CD8 will lead to a greater understanding of inflammation and host defense.
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PMID:Mechanisms of macrophage stimulation through CD8: macrophage CD8alpha and CD8beta induce nitric oxide production and associated killing of the parasite Leishmania major. 963 15

Progressive renal diseases lead to prolonged glomerular hypertension, which induces the proliferation of mesangial cells. This proliferation is thought to be involved in the development of renal injury. Here we investigate mitogen-activated protein kinase (MAPK) activation and cell proliferation in mesangial cells under conditions of high pressure. After pressure-load, the phosphorylation level of MAPK (at Tyr-204) increases rapidly with a peak at 1 min, although the amount of MAPK remains almost constant during pressure-load. To confirm the activation of MAPK, we carried out an immunoprecipitation-kinase assay. MAPK activity during pressure-load shows kinetics similar to that of the tyrosine phosphorylation. In contrast, c-Jun N-terminal kinase 1 (JNK1) phosphorylation falls below basal levels in response to high pressure. Immunocytochemical observations show phosphorylated MAPK in the nucleus at 10 min. The expression of c-Fos, a nuclear transcription factor, is induced by high pressure, and the induction is significantly inhibited by PD98059 (50 microM), an upstream MAPK/extracellular signal-regulated kinase kinase (MEK) inhibitor of MAPK. The expression of the c-Jun that is induced by JNK1 activation remains unchanged during pressure-load. MAPK phosphorylation and cell proliferation by applied pressure are significantly inhibited by genistein, a tyrosine kinase inhibitor in a dose-dependent manner, but not by protein kinase C inhibitors, chelerythrine and GF109203X. Genistein also blocks pressure-induced tyrosine phosphorylation of proteins with molecular masses of 35, 53, and 180 kDa. To clarify the physiological role in MAPK activation under high pressure conditions, we transfected antisense MAPK DNA into mesangial cells. The antisense DNA (2 microM) inhibited MAPK expression by 80% compared with expression in the presence of sense or scrambled DNA, and significantly blocked pressure-induced cell proliferation. Treatment of cells with MEK inhibitor also produced a similar result. MEK inhibitor strongly suppresses DNA synthesis induced by pressure-load. Cyclin D1 expression is significantly increased under high pressure conditions, and the increase is blocked by treatment with MEK inhibitor. These findings show that pressure-load, a novel activator of MAPK, induces the activation of tyrosine kinases, and enhances the proliferation of mesangial cells, probably through cyclin D1 expression.
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PMID:Applied pressure enhances cell proliferation through mitogen-activated protein kinase activation in mesangial cells. 964 52

This study aims to investigate potential mechanisms involved in the stimulatory effect of amniotic fluid on prostaglandin production by fetal membranes. A cell culture study of amnion and chorion was obtained following elective caesarean section, incubated with amniotic fluid collected at term (37-42 weeks' gestation) following either spontaneous labour (n = 6) or elective caesarean section (n = 6). The effect of addition of cycloheximide and actinomycin D (inhibitors of translation and transcription respectively), and staurosporine and genistein (inhibitors of protein kinase C and tyrosine kinase respectively) to these cultures was investigated. ANOVA was employed for statistical analysis. Cycloheximide and staurosporine significantly inhibited the stimulatory effect of spontaneous labour and elective section amniotic fluid on PGE2 production by amnion, and PGEM production by chorion. Genistein significantly inhibited the stimulatory effect of spontaneous labour amniotic fluid on PGE2 and PGEM production by amnion and chorion respectively. The stimulatory effect of amniotic fluid on prostaglandin production is dependent on new protein synthesis, presumably cyclooxygenase (COX), and stimulation of cell signal transduction pathways involving protein kinase C and tyrosine kinase.
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PMID:Mechanisms involved in the stimulatory effect of amniotic fluid on prostaglandin production by human fetal membranes. 969 Jul 15

In opossum kidney (OK) cells, L-dihydroxyphenylalanine (10 microM) raised dopamine to 10 nM and inhibited Na-inorganic phosphate (Pi) uptake 20% (P = 0.001). Inhibition was completely blocked by carbidopa or SCH23390. Dopamine (1 microM) inhibited uptake 55% (half-maximal inhibition, 0.03 microM). Fenoldopam (0.1 microM, DA1 agonist) inhibited uptake 45 +/- 2%. DA1 antagonists (SKF83566 and SCH23390), but not DA2-antagonist (sulpiride), blocked dopamine inhibition. Quinpirole (DA2 agonist) did not modify Pi uptake. Bisindolylmaleimide (10 microM), a protein kinase C inhibitor, blocked inhibition of Pi uptake by phorbol ester but had no effect on the response to dopamine. Dopamine inhibited Pi uptake in cells that had been exposed to phorbol ester for 18 to 24 h. Dopamine inhibition was not reduced by 1 microM U73,122 but was reduced 20% by 10 microM, which is 10 times the concentration reported to completely inhibit phospholipase C in OK cells. Adenylate cyclase inhibitors SQ 22536 (100 microM) and 2,5-dideoxyadenosine (100 microM) reduced dopamine-stimulated cAMP production, but not dopamine inhibition of Pi uptake. Rp-cAMPS counteracted the inhibition of Pi uptake by Sp-cAMPS but had no effect on the dopamine response. H-89 inhibited dopamine-stimulated protein kinase A activity, but neither H-89 nor H-9 alone or with bisindolylmaleimide altered dopamine inhibition of Pi uptake. Genistein and herbimycin A (tyrosine kinase inhibitors) reduced Pi uptake. However, dopamine, a benzoquinone like several tyrosine kinase inhibitors, did not inhibit tyrosine kinase activity. Thus, dopamine inhibited Pi uptake in this OK cell clone by activating a G protein-linked pathway that operates independently from adenylyl cyclase, protein kinase A, protein kinase C, and protein tyrosine kinase.
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PMID:Does dopamine use several signal pathways to inhibit Na-Pi transport in OK cells? 972 68

Among its diverse biological actions, the vasoactive peptide bradykinin (BK) induces the transcription factor AP-1 and proliferation of mesangial cells (S. S. El-Dahr, S. Dipp, I. V. Yosipiv, and W. H. Baricos. Kidney Int. 50: 1850-1855, 1996). In the present study, we examined the role of protein tyrosine phosphorylation and the mitogen-activated protein kinases, ERK1/2,in mediating BK-induced AP-1 and DNA replication in cultured rat mesangial cells. BK (10(-9) to 10(-7) M) stimulated a rapid increase in tyrosine phosphorylation of multiple proteins with an estimated molecular mass of 120-130, 90-95, and 44-42 kDa. Immunoblots using antibodies specific for ERK or tyrosine-phosphorylated ERK revealed a shifting of p42 ERK2 to a higher molecular weight that correlated temporally with an increase in tyrosine-phosphorylated ERK2. Genistein, a specific tyrosine kinase inhibitor, prevented the phosphorylation of ERK2 by BK. In-gel kinase assays indicated that BK-induced tyrosine phosphorylation of ERK2 is accompanied by fourfold activation of its phosphotransferase activity toward the substrate PHAS-I (P < 0.05). Furthermore, BK stimulated a 2.5-fold increase (P < 0.05) in phosphorylation of Elk-1, a transcription factor required for growth factor-induced c-fos transcription. In accord with the stimulation of Elk-1 phosphorylation, BK induced c-fos gene expression and the production of Fos/AP-1 complexes. In addition, thymidine incorporation into DNA increased twofold (P < 0. 05) following BK stimulation. Each of these effects was blocked by tyrosine kinase inhibition with genistein or herbimycin A. Similarly, antisense oligodeoxynucleotide targeting of ERK1/2 mRNA inhibited BK-stimulated DNA synthesis. In contrast, protein kinase C inhibition or depletion had no effect on BK-induced c-fos mRNA, AP-1-DNA binding activity, or DNA synthesis. Collectively, these data demonstrate that BK activates the ERK-->Elk-1-->AP-1 pathway and that BK mitogenic signaling is critically dependent on protein tyrosine phosphorylation.
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PMID:Bradykinin stimulates the ERK-->Elk-1-->Fos/AP-1 pathway in mesangial cells. 972 6

Taxol-induced polymerization of tubulin into stable microtubules and cell cycle metaphase arrest have been demonstrated to result in internucleosomal DNA fragmentation and morphological features of apoptosis in human leukemia cells. Recent studies have also shown that Taxol-induced apoptosis, but not Taxol-induced microtubular bundling or mitotic arrest, is significantly inhibited in cells that overexpress the bcl-2 gene product p26BCL-2. In the present studies we examined the effects of several modulators of activities of protein kinases on Taxol-induced DNA fragmentation and apoptosis in human pre-B leukemia 697 cells transfected with the cDNA of the bcl-2 gene and expressing high intracellular levels of p26BCL-2 (697/BCL-2 cells). Treatment with 0.1-1.0 microM MTaxol for 24 h produced prolonged mitotic arrest of control 697/neo cells, which had been transfected with the neomycin resistance gene. This resulted in apoptosis-associated large DNA fragments ranging between 5 and 200 kb and internucleosomal DNA fragmentation. Cotreatment with the phorbol ester phorbol dibutyrate (PdBU) significantly reduced Taxol-induced internucleosomal and large DNA fragmentation and inhibited apoptosis of 697/neo cells. In contrast, a combined exposure to Taxol and staurosporine (ST; 5 or 50 ng/ml), a potent inhibitor of protein kinase C and other kinases, significantly increased DNA fragmentation and apoptosis of 697/neo cells. Additionally, in 697/BCL-2 cells, ST partially overcame the suppressive effects of high p26BCL-2 levels on Taxol-induced apoptosis. Cotreatment with the tyrosine kinase inhibitor Genistein (30 microM) markedly inhibited Taxol-induced DNA fragmentation and apoptosis of 697/neo cells. However, it is noteworthy that the modulations of Taxol-induced DNA fragmentation and apoptosis by PdBU, ST, and Genistein occurred without significant effects on Taxol-mediated mitotic arrest of 697/neo cells. These agents also did not affect intracellular p26BCL-2 levels in 697/neo or 697/BCL-2 cells. These findings indicate that Taxol-induced apoptosis can be modulated by agents that affect the activities of protein kinases, and these effects are not mediated by modulations of Taxol-induced mitotic arrest or by alterations of intracellular p26BCL-2 levels.
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PMID:Effects of modulators of protein kinases on taxol-induced apoptosis of human leukemic cells possessing disparate levels of p26BCL-2 protein. 981 37

The aim of these studies was to examine the involvement of tyrosine phosphorylation in the signal transduction pathways and secretory events that are promoted by receptor agonists acting on rat parotid acinar cells. Fluid secretion by parotid acinar cells is initiated by the binding of neurotransmitters to GTP(G)-protein-coupled receptors that are linked to phospholipase C, which hydrolyzes phosphatidlyinositol 4,5-bisphosphate to diacylglycerol and inositol 1,4,5-trisphosphate. Although growth factors produce large changes in tyrosine phosphorylation of multiple proteins involved in proliferation and other cellular processes, tyrosine phosphorylation is not considered to be a general phenomenon of G-protein-coupled receptor activation. However, our results shown that carbachol (a muscarinic acetylcholine receptor agonist), and ligands to other phospholipase C-linked receptors, promoted a rapid increase in the tyrosine phosphorylation of protein kinase Cdelta (PKCdelta), a member of the PKC family of proteins. Phorbol 12-myristate 13-acetate, which binds to the site on PKCdelta to which the endogenous activator sn-1,2-diacylglycerol binds, also increased the tyrosine phosphorylation of PKCdelta. Genistein and staurosporine, two protein kinase inhibitors, blocked the tyrosine phosphorylation of this protein. Thus, PKCdelta becomes tyrosine phosphorylated in response to receptor activation, and this event appears to involve both diacylglycerol production and protein tyrosine kinase activity. This may contribute to early physiological events, including alterations in fluid secretion, that are initiated by neurotransmitters acting on the parotid salivary gland.
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PMID:Involvement of protein kinases and phosphatases in tyrosine phosphorylation of PKCdelta in rat parotid acinar cells exposed to secretory stimuli. 982 17


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