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

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

Protein kinases are known to undergo phosphorylation to regulate their activity. To determine whether the protein kinase activity of p37v-mos was similarly regulated, we investigated the influence of two well known protein kinases, namely protein kinase C and protein kinase A, on the activity of p37v-mos in vivo. NIH3T3 cells chronically transformed with Moloney murine sarcoma virus 124 were treated with high concentrations (200-400 nM) of phorbol 12-myristate 13-acetate (PMA) for 24-48 h, concentrations known to result in the total loss of protein kinase C by causing its translocation from the cytosol to cell membranes where it is downregulated. PMA treatment caused a drastic decrease in the protein kinase activity of p37v-mos without affecting its steady state level. Similar results were obtained with p85gag-mos expressed in ts110 Mo-MuSV transformed NRK cells. Control treatment with an inactive analogue of PMA, 4-alpha phorbol 12,13-didecanoate, had no effect on the p37v-mos protein kinase activity. Treatment of cells with a direct chemical inhibitor of protein kinase C, H-7 (1-(5-isoquinoline sulfonyl)-2-methylpiperazine dihydrochloride), approximately halved p37v-mos kinase activity, although the drug did not inhibit p37v-mos kinase activity directly in vitro. In contrast to the PMA effect, in vivo activation of protein kinase A by 8-(4-chlorophenylthio)-adenosine 3',5' cyclic monophosphate did not affect p37v-mos protein kinase activity levels. These findings indicate that the protein kinase C pathway but not the protein kinase A pathway modulates v-mos protein kinase activity.
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PMID:Evidence for involvement of the protein kinase C pathway in the activation of p37v-mos protein kinase. 216 30

Drugs thought to inhibit the actions of protein kinase C (PKC) and cAMP dependent protein kinase (A-kinase) were infused intrathecally into the subarachnoid space of the lumbar region of the spinal cord, and the effects on acoustic startle were measured. Previous work has shown that intrathecal infusion of drugs thought to increase cAMP increase the startle response. The present experiment evaluated whether inhibition of A-kinase would prevent this effect. Rats were infused with the isoquinoline sulfonamide, H-8 (360 nmol) or vehicle (50% dimethyl sulfoxide), 30 min prior to infusion of 100 nmol of dibutyryl cAMP. By itself, H-8 had little effect on startle, but completely blocked the normal excitatory effect of dibutyryl cAMP on startle. In contrast, the isoquinoline sulfonamide, H-7, which is less active in blocking A-kinase, but more active in blocking PKC, did not block dibutyryl cAMP. Moreover, H-8 did not block the excitatory effect of intrathecal infusion of the 5-HT1A receptor agonist, 8-OH-dipropylaminotetraline (8-OH-DPAT). Thus, the blockade of dibutyryl cAMP by H-8 appears somewhat specific and suggests an involvement of A-kinase in the excitatory effects of dibutyryl cAMP on the acoustic startle response. In a second experiment, it was found that administration of the isoquinoline sulfonamide H-7 caused a marked, dose-dependent (150-800 nmol) facilitation of the startle reflex in comparison with its vehicle. Tris buffer (0.1 M). Like H-7, another PKC inhibitor, GT1b (20 nmol) produced a marked increase in the startle reflex versus its vehicle, 0.01 M phosphate buffer.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Blockade of the spinal excitatory effect of cAMP on the startle reflex by intrathecal administration of the isoquinoline sulfonamide H-8: comparison to the protein kinase C inhibitor H-7. 217 10

A recombinant N-ras oncogene, under the transcriptional control of a corticosteroid-inducible mouse mammary tumor virus (MMTV) promoter, has been stably transfected into a PC12 rat pheochromocytoma subline. This cell line, designated UR61, undergoes N-ras-induced neurite outgrowth and cessation of division when treated with dexamethasone (Guerrero et al.: Biochemical and Biophysical Research Communications 150:1185-1192, 1988). We have employed the UR61 cell line as a model for ras oncogene-induced neuronal differentiation. In UR61 cells, dexamethasone-induced expression of the recombinant N-ras gene resulted in time-dependent expression of ornithine decarboxylase enzyme (ODC) activity. Prompted by recent reports of possible functional (Lacal et al.: Molecular and Cellular Biology 7:4146-4149, 1987; Wolfman and Macara: Nature 325: 359-361, 1987) and direct (Jeng et al.: Biochemical and Biophysical Research Communications 145:782-788, 1987) interactions between oncogene ras-coded p21 and protein kinase C (PK-C; Ca++/phospholipid-dependent protein kinase), we employed the protein kinase inhibitor H-8 (N-[2-(methylamino)ethyl]-5-isoquinoline sulfonamide dihydrochloride) and phorbol 12,13-dibutyrate (PDBu) to investigate this putative interaction in the UR61 cells, where ODC activity and neurite outgrowth were used as indicators of oncogenic N-ras action. Treatment of UR61 cells with PDBu depleted cells of PK-C and failed to promote neurite outgrowth but enhanced N-ras-induced neurite outgrowth and ODC activity. H-8, which suppressed ODC induction by forskolin and phorbol myristate acetate, enhanced both N-ras-induced ODC activity and neurite outgrowth. Inhibition of ODC activity by difluoromethylornithine (DFMO) did not suppress oncogenic ras-induced neurite outgrowth, suggesting that these two ras-triggered events are mechanistically independent. These findings suggest that certain actions of N-ras can occur in cells depleted of PK-C, and thus, the role of PK-C in ras-induced differentiation differs from its role in ras-induced mitogenesis and transformation.
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PMID:Potentiation of oncogenic N-ras-induced neurite outgrowth and ornithine decarboxylase activity by phorbol dibutyrate and protein kinase inhibitor H-8. 218 Sep 65

The effects of purified Ca2+, phospholipid-dependent protein kinase (C-kinase) were studied on adenylate cyclase activity from rat brain striatum. C-kinase treatment of the membranes stimulated adenylate cyclase activity, the maximal stimulation between 50-80% was observed at 3.5 U/ml, whereas the catalytic subunit of cAMP dependent protein kinase did not show any effect on enzyme activity. The inclusion of Ca2+ and phosphatidyl serine did not augment the percent stimulation of adenylate cyclase by C-kinase, however EGTA inhibited the stimulatory effect of C-kinase on enzyme activity. Furthermore, the known inhibitors of C-kinase such as polymyxin-B and 1-(5-Isoquinoline sulfonyl)-2-methylpiperazine dihydrochloride (H-7) also inhibited the stimulatory effect of C-kinase on adenylate cyclase activity. In addition, in the presence of GTP the stimulatory effects of C-kinase on basal and N-Ethylcarboxamide adenosine- (NECA-), dopamine-(DA) and forskolin- (FSK) sensitive adenylate cyclase activities were augmented. On the other hand, the inhibitory effect of high concentrations of GTP on enzyme activity was attenuated by C-kinase treatment. In addition, oxotremorine inhibited adenylate cyclase activity in a concentration dependent manner, with an apparent Ki of about 10 microM and C-kinase treatment almost completely abolished this inhibition. These data suggest that C-kinase may play an important role in the regulation of adenylate cyclase activity possibly by interacting with a guanine nucleotide regulatory protein.
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PMID:Modulation of adenylate cyclase activity by Ca2+, phospholipid-dependent protein kinase in rat brain striatum. 230 80

A newly synthesized compound, H-87, N-[2-(p-bromo cinnamylmethylamino)ethyl]-5-isoquinolinesulfonamide was found to be a potent and selective inhibitor of cyclic AMP-dependent protein kinase. The effects of H-87 on in vitro sensitivities of various P388 murine leukemia cell lines resistant to several antitumor agents were examined. H-87 significantly potentiated the cytotoxic effects of Adriamycin (ADR), daunorubicin (DAU), vincristine (VCR) and vinblastine (VBL) on P388 cells resistant to these antitumor agents but hardly influenced the effects of mitomycin C (MMC), 5-fluorouracil (5-FU) and cisplatin (CDDP) on ADR-resistant P388 cells (P388/ADR) and P388 phenotypes resistant to the corresponding antitumor agents. H-87 promoted the accumulation of VBL much more in P388/ADR cells than in the sensitive cells by inhibiting the energy-dependent extrusion of the antitumor agent from the cells. These results suggest that this novel isoquinoline-sulfonamide derivative, H-87, overcomes the multidrug resistance by inhibiting the phosphorylation of an outward drug transport system through cyclic AMP-dependent protein kinase.
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PMID:Circumvention of multidrug resistance in P388 murine leukemia cells by a novel inhibitor of cyclic AMP-dependent protein kinase, H-87. 233 96

Perturbing the changes in protein phosphorylation accompanying the first cleavage can inhibit the appearance of a set of proteins whose synthesis is inhibited by alpha-amanitin (transcription-requiring proteins, TRPs) (W. T. Poueymirou and R. M. Schultz, 1987, Dev. Biol. 121, 489-498); synthesis of the TRPs is likely to represent activation of transcription of the embryonic genome that occurs at the 2-cell stage during mouse development. In the present study, we report the effects of three different inhibitors of the cAMP-dependent protein kinase, N-[2-(methylamino)ethyl]-5-isoquinoline-sulfonamide (H8), (Rp)-cAMPs, and protein kinase inhibitor (PKI), each of which inhibits the kinase by a different mechanism, on cleavage of 2-cell embryos and synthesis of the TRPs. Two-cell embryos possess PK-A activity, which is inhibited by each of these inhibitors. Both H8 and (Rp)-cAMPs inhibit cleavage of 2-cell embryos in a concentration-dependent manner; similar concentrations of H7, which is a less potent inhibitor of PK-A, do not inhibit cleavage. H8 and (Rp)-cAMPS inhibit in a concentration-dependent manner TRP synthesis, whereas higher concentrations of H7 are required to inhibit TRP synthesis. Microinjected PKI also inhibits synthesis of the TRPs. In addition, H8 inhibits the accumulation of translatable messenger RNAs that are likely to encode for the TRPs. Last, H8, but not H7, inhibits the phosphorylation of a phosphoprotein in 2-cell embryos. Results of these studies suggest a role for protein phosphorylation catalyzed by cAMP-dependent protein kinase in regulating transcription in the early mouse embryo.
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PMID:Regulation of mouse preimplantation development: inhibition of synthesis of proteins in the two-cell embryo that require transcription by inhibitors of cAMP-dependent protein kinase. 254 2

Interleukin 2 production by activated Jurkat T cells is markedly decreased by prostaglandin E2 (PGE2). The target of PGE2 action has been investigated in the present study. Among the biochemical events occurring after CD3.TCR triggering by anti-CD3 monoclonal antibody, phosphorylation of two cytosolic proteins, pp21 and pp23, was strongly inhibited by PGE2, forskolin, and 8-bromo-cAMP, whereas anti-CD3 monoclonal antibody-induced CD3.TCR modulation and Ca2+ influx were not affected. The inhibition of both pp21 and pp23 phosphorylation and interleukin 2 synthesis by PGE2 can be largely reversed by the cAMP-dependent protein kinase inhibitor, N-[2-(methylamino)-ethyl-1]-5-isoquinoline sulfonamide. Together with the demonstration of a cAMP-dependent protein kinase activity in Jurkat T cells, these results are consistent with the participation of the cAMP-dependent protein kinase mediating the inhibitory action of PGE2, probably through the inhibition of pp21 and pp23 phosphorylation. Thus, it appears that the modulation of the phosphorylation of these cytosolic proteins represents an essential step in the regulation of T lymphocyte activation.
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PMID:Modulation of T cell activation by differential regulation of the phosphorylation of two cytosolic proteins. Implication of both Ca2+ and cyclic AMP-dependent protein kinases. 254 97

The inhibition of protein kinase activity by the isoquinoline sulfonamide, H-8, lengthens the period of the Bulla ocular circadian rhythm in a dose-dependent manner. In addition, the phosphorylation of 5 proteins is markedly affected by H-8. The observed correlation between H-8's period lengthening effects, and its effects on the phosphorylation of specific proteins, suggests that: (1) these proteins are candidate components regulating the period of the circadian rhythm; and (2) the daily changes in membrane potential underlying the circadian rhythm are mediated by similar mechanisms that serve to change neural function in other systems; modulation of protein kinases.
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PMID:Kinase inhibition lengthens the period of the circadian pacemaker in the eye of Bulla gouldiana. 259 24

Exposure of human monocytes to 95% normobaric oxygen (O2) was used as an in vitro oxidative injury model to study the effects of the O2-derived species produced by phagocytes at inflammatory sites on monocyte IL-1 production. Exposure to O2 enhanced production by monocytes of IL-1-like activity whether the adherent cells were cultured in the presence of opsonized zymosan, LPS or medium alone. This O2-induced increase in production of IL-1 activity was inhibited by cycloheximide and thus resulted from de novo protein synthesis. Furthermore, the increase was prevented by the addition of the protein kinase inhibitor N-2-methylaminoethyl-5-isoquinoline sulfonamide dihydrochloride (H8). Following exposure to O2, Ca2+/phospholipid-independent protein kinase activity increased in comparison to air-exposed monocytes, whereas the dependent form decreased. Since the Ca2+/phospholipid-independent form is known to derive from the dependent form (protein kinase C) by proteolysis in the presence of a thiol proteinase, our results suggest that oxidative injury stimulates thiol proteinase activity and enhances production of IL-1 activity by human monocytes partly by interfering with protein kinase C metabolism. Among the consequences of the generation of O2-derived species by phagocytes in inflammatory sites, the augmentation of the production of IL-1-like activity could amplify the inflammatory response.
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PMID:Oxidative injury amplifies interleukin-1-like activity produced by human monocytes. 261 99

The effects of the isoquinoline sulfonamides, a class of synthetic protein kinase inhibitors, namely 1-(5-isoquinoline sulfonyl)-2-methylpiperazine dihydrochloride (H7), N-[2-(methylamino)ethyl]-5-isoquinoline sulfonamide dihydrochloride (H8), N-(2-aminoethyl)-5-isoquinoline sulfonamide dihydrochloride (H9), and N-(2-guanidinoethyl)-5-isoquinoline sulfonamide hydrochloride (HA1004), on the lytic activity of in vivo-produced (H-2b anti-H-2d alloimmune) cytotoxic T lymphocytes (CTL) were investigated. The hierarchy of inhibition of lysis shown by these compounds resembled that of their inhibition of Ca2+/phospholipid-dependent enzyme (protein kinase C). H7 has the highest affinity for protein kinase C (Hidaka, H., Inagaki, M., Kawamoto, S., and Sasaki, Y. (1984) Biochemistry 23, 5036-5041) and gave the greatest inhibition of lysis by CTL. HA1004 has the weakest affinity for protein kinase C and gave very little inhibition of lysis, whereas H8 and H9 showed intermediate inhibition of lysis. In addition, the effect of the isoquinoline sulfonamides on cellular proliferation was examined. Interestingly, the pattern of inhibition observed for both lymphocytes and tumor cells closely mimicked the effects of these compounds on protein kinase C activity. These results demonstrate that modulation of an early biochemical signal affects both short-term (e.g. CTL-mediated lysis) and long-term (e.g. cellular proliferation) events. These data provide further evidence for the integral role of protein kinase C in the activation of the lytic signal in CTL. In addition, suggestive evidence is provided that protein kinase C, or some other enzyme with similar sensitivity to the isoquinoline sulfonamides, plays an important role in cellular proliferation.
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PMID:Inhibition of cytotoxic T lymphocyte-mediated lysis and cellular proliferation by isoquinoline sulfonamide protein kinase inhibitors. Evidence for the involvement of protein kinase C in lymphocyte function. 278 20


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