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:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin and hepatocyte growth factor (HGF) induced morphologically different membrane rufflings in KB cells. Insulin-induced membrane ruffling was inhibited by microinjection of rho GDI, an inhibitory GDP/GTP exchange regulator for both rho p21 and rac p21 small GTP-binding proteins, but not inhibited by microinjection of botulinum exoenzyme C3, known to selectively ADP-ribosylate rho p21 and to impair its function. This rho GDI action was prevented by comicroinjection with guanosine 5'-(3-O-thio)triphosphate (GTP gamma S)-bound rac1 p21. In contrast, HGF-induced membrane ruffling was inhibited by microinjection of rho GDI or C3. This rho GDI action was prevented by comicroinjection with GTP gamma S-bound rhoA p21, and this C3 action was prevented by comicroinjection with GTP gamma S-bound rhoAIle-41 p21, which is resistant to C3. Microinjection of either GTP gamma S-bound rac1 p21 or rhoA p21 alone induced membrane ruffling in the absence of the growth factors. The rac1 p21-induced membrane ruffling was morphologically similar to the insulin-induced kind, whereas rhoA p21-induced ruffling was apparently different from both the insulin- and HGF-induced kinds. Membrane ruffling was also induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), a protein kinase C-activating phorbol ester, but not by Ca2+ ionophore or microinjection of a dominant active Ki-ras p21 mutant (Ki-rasVal-12 p21). The phorbol ester-induced membrane ruffling was morphologically similar to the rhoA p21-induced kind and inhibited by microinjection of rho GDI or C3. These results indicate that rac p21 and rho GDI are involved in insulin-induced membrane ruffling and that rho p21 and rho GDI are involved in HGF- and phorbol ester-induced membrane rufflings.
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PMID:rac p21 is involved in insulin-induced membrane ruffling and rho p21 is involved in hepatocyte growth factor- and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced membrane ruffling in KB cells. 813 48

As recently reported, B-003 (6-S-hexadecyl-2-methoxythioascorbic acid) shows strong inhibition of the N-formylmethionylleucyl phenylalanine (fMLP)-stimulated neutrophil superoxide production and degranulation ex vivo, which is not correlated with its antioxidant properties. Structure-activity studies with 12 derivatives. together with permeation studies, pointed to a process for uptake of B-003 but not its regioisomer B-015 into neutrophils and revealed the importance of the free acidic enolic hydroxyl group in the 3-position of ascorbic acid and of a long chain alkyl group having a chain length of C16-C18 for effective inhibition. We now report that B-003 also strongly suppressed C5a-, concanavalin A-, and calcium ionophore A23187-stimulated superoxide formation, whereas protein kinase C-mediated activation by phorbol ester remained unaffected. The fMLP- or C5a-induced calcium mobilization form intracellular stores of fura-2-loaded cells, as well as the fMLP- or A23187-triggered release of [14C] arachidonate from prelabeled neutrophils, was not affected by B-003. The observed release of GSH was not causally related to inhibition of the oxidative burst, because GSH depletion by 1-chloro-2,4-dinitrobenzene was without effect on the fMLP-stimulated superoxide formation or on the inhibitory effect of B-003. In a cell-free system, consisting of a light membrane fraction and a cytosol fraction from resting neutrophils, B-003 inhibited the arachidonate-induced assembly of the NADPH-oxidase under conditions where particulate NADPH-oxidase from phorbol ester-preactivated neutrophils and catalytically active cell-free assembled oxidase were not affected. The inhibitory effect was more pronounced when the system was incubated in the presence of the G protein activator guanosine-5'-O-(3-thio)triphosphate (GTP gamma S). [35S]GTP gamma S binding studies excluded displacement of the G protein activator from guanine nucleotide binding sites by B-003. In vitro assembly/co-sedimentation experiments in the presence of GTP gamma S revealed a 2-fold increase in a small cytosolic G protein with a molecular mass of 21 kDa (p21) in pelleted membranes, as detected by [35S]GTP gamma S protein blot probing, that was not affected by B-003. Structure-activity relationship studies of the effects of various 6-S-alkylascorbyl derivatives on the GTP gamma S/arachidonate-triggered assembly of the NADPH-oxidase showed strong dependence of the inhibition on the alkyl chain length, with long chain alkyl derivatives (C16 and C18) being most effective.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Inhibition of NADPH-oxidase activity in human polymorphonuclear neutrophils by lipophilic ascorbic acid derivatives. 819 99

Rabphilin-3A is a putative target molecule for rab3A p25/smg p25A, which is a member of a ras p21-related small GTP-binding protein and implicated in neurotransmitter release from the synapse. Rabphilin-3A has two copies of an internal repeat that are homologous to the C2 domains of protein kinase C, synaptotagmin, and phospholipase A2, which are known to bind to phospholipid in a Ca(2+)-dependent manner. In the current study, we have investigated the functional domains or rabphilin-3A by use of three recombinant proteins as follows: full rabphilin-3A (1-704 amino acids), an N-terminal fragment (1-280 amino acids), and a C-terminal fragment containing the C2 domains (281-704 amino acids). Both rabphilin-3A and the C-terminal fragment bound to phospholipid in the presence of Ca2+, but the N-terminal fragment did not bind to phospholipid. 45Ca2+ bound to rabphilin-3A and the C-terminal fragment only in the presence of phospholipid but did not bind to the N-terminal fragment. The GTP gamma S-bound form of rab3A p25 bound to both rabphilin-3A and the N-terminal fragment but did not bind to the C-terminal fragment. These results indicate that rabphilin-3A has at least two functionally different domains, the N-terminal rab3A p25-binding and C-terminal phospholipid- and Ca(2+)-binding domains.
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PMID:Two functionally different domains of rabphilin-3A, Rab3A p25/smg p25A-binding and phospholipid- and Ca(2+)-binding domains. 826 55

Hepatocyte growth factor (HGF) induced motility of cultured mouse keratinocytes (308R cells). This HGF-induced cell motility was inhibited by microinjection of either rho GDI, an inhibitory GDP/GTP exchange protein for rho p21 small GTP-binding protein, or a botulinum exoenzyme C3 which is known to selectively impair the function of rho p21 by ADP-ribosylating its effector domain. The rho GDI action was prevented by comicroinjection with the guanosine 5'-(3-0-thio)triphosphate (GTP gamma S)-bound active form of rhoA p21, and the C3 action was prevented by comicroinjection with a rhoA p21 mutant (rhoAIle41 p21) which is resistant to the C3 action. The HGF-induced cell motility was not inhibited by microinjection of a dominant negative rac1 p21 mutant (rac1Asn17 p21) or a dominant negative Ki-ras p21 mutant (Ki-rasAsn17 p21). Microinjection of the GTP gamma S-bound form of rac1 p21 or a dominant active Ki-ras p21 mutant (Ki-rasVal12 p21) did not induce cell motility. These results indicate that both rho p21 and rho GDI, but neither rac p21 nor ras p21, are involved in the HGF-induced cell motility. However, microinjection of the GTP gamma S-bound form of rhoA p21 alone did not induce cell motility in the absence of HGF, suggesting that activation of rho p21 is necessary but not sufficient for the HGF-induced cell motility. The HGF-induced cell motility was mimicked by 12-0-tetradecanoyl-phorbol-13-acetate, a protein kinase C-activating phorbol ester, but not by Ca2+ ionophore. The phorbol ester-induced cell motility was also inhibited by microinjection of rho GDI or C3. These results indicate that both rho p21 and rho GDI are also involved in the phorbol ester-induced cell motility.
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PMID:Involvement of Rho p21 small GTP-binding protein and its regulator in the HGF-induced cell motility. 830 89

Nuclear factor kappa B (NF-kappa B) plays a critical role in the regulation of a number of genes. NF-kappa B is a heterodimer of 50- and 65-kDa subunits sequestered in the cytoplasm complexed to inhibitory protein I kappa B. Following stimulation of cells, I kappa B dissociates from NF-kappa B, allowing its translocation to the nucleus, where it carries out the transactivation function. The precise mechanism controlling NF-kappa B activation and the involvement of members of the protein kinase C (PKC) family of isotypes have previously been investigated. It was found that phorbol myristate acetate, (PMA) which is a potent stimulant of phorbol ester-sensitive PKC isotypes, activates NF-kappa B. However, the role of PMA-sensitive PKCs in vivo is not as apparent. It has recently been demonstrated in the model system of Xenopus laevis oocytes that the PMA-insensitive PKC isotype, zeta PKC, is a required step in the activation of NF-kappa B in response to ras p21. We demonstrate here that overexpression of zeta PKC is by itself sufficient to stimulate a permanent translocation of functionally active NF-kappa B into the nucleus of NIH 3T3 fibroblasts and that transfection of a kinase-defective dominant negative mutant of zeta PKC dramatically inhibits the kappa B-dependent transactivation of a chloramphenicol acetyltransferase reporter plasmid in NIH 3T3 fibroblasts. All these results support the notion that zeta PKC plays a decisive role in NF-kappa B regulation in mammalian cells.
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PMID:A dominant negative protein kinase C zeta subspecies blocks NF-kappa B activation. 833 14

In a previous study (H. Shirataki, K. Kaibuchi, T. Yamaguchi, K. Wada, H. Horiuchi, and Y. Takai, J. Biol. Chem. 267:10946-10949, 1992), we highly purified from bovine brain crude membranes the putative target protein for smg p25A/rab3A p25, a ras p21-related small GTP-binding protein implicated in neurotransmitter release. In this study, we have isolated and sequenced the cDNA of this protein from a bovine brain cDNA library. The cDNA had an open reading frame encoding a protein of 704 amino acids with a calculated M(r) of 77,976. We tentatively refer to this protein as rabphilin-3A. Structural analysis of rabphilin-3A revealed the existence of two copies of an internal repeat that were homologous to the C2 domain of protein kinase C as described for synaptotagmin, which is known to be localized in the membrane of the synaptic vesicle and to bind to membrane phospholipid in a Ca(2+)-dependent manner. The isolated cDNA was expressed in COS7 cells, and the encoded protein was recognized with an anti-rabphilin-3A polyclonal antibody and was identical in size with rabphilin-3A purified from bovine brain by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Moreover, both rabphilin-3A purified from bovine brain and recombinant rabphilin-3A made a complex with the GTP gamma S-bound form of rab3A p25 but not with the GDP-bound form of rab3A p25. Immunoblot and Northern (RNA) blot analyses showed that rabphilin-3A was highly expressed in bovine and rat brains. These results indicate that rabphilin-3A is a novel protein that has C2 domains and selectively interacts with the GTP-bound form of rab3A p25.
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PMID:Rabphilin-3A, a putative target protein for smg p25A/rab3A p25 small GTP-binding protein related to synaptotagmin. 838 2

The CDK-inhibitor p21WAF1/CIP1 has been implicated as a growth arrest mediator in p53-tumour suppression, cellular senescence and terminal differentiation. Cell type specific differences in p53-independent p21 expression and cell cycle arrest were found following treatment of human tumour cell lines with serum, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), or okadaic acid (OA). TPA induced p21 in ML1, K562 and HL60 leukemia cells, whereas OA induced p21 in SW480 and GM4723 carcinoma cells as well as in leukemic cells. In addition, TPA- and serum- but not OA-induced cell cycle arrest was reversed upon return of p21 to basal levels. To further investigate the mechanisms underlying p53-independent regulation of p21, the transcription inhibitor, Actinomycin D (AMD), was used to block p21 expression. The results showed a complete inhibition of p21 mRNA and protein induction by TPA or adriamycin but little effect on p21 mRNA induced by OA in the presence of AMD. These results suggested that TPA-induced p21 expression requires transcription initiation, while a post-transcriptional mechanism may be involved in OA-induction as well. Transient transfection assays with p21 promoter-luciferase reporters and TPA or OA treatment further confirmed that TPA, and to a lesser extent, OA, initiated transcription of p21. Finally, the protein kinase C inhibitor, staurosporine, was found to interfere with p21 induction and prevent cell cycle arrest following treatment with TPA but not OA, suggesting a requirement for PKC in TPA activation of p21 expression.
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PMID:Regulation of p21WAF1/CIP1 expression by p53-independent pathways. 862 72

UV irradiation of mammalian cells results in the activation of transcription factors which mediate induction of early response genes designed to repair and minimise the damage sustained by the cell. Evidence from studies in HeLa cells suggest that UVC regulates NF-kappa B activity via tyrosine kinases and activation of Ras and Raf kinase. In this study we have used a previously characterized TPA-responsive element (VLTRE) that binds Rel/NF-kappa B proteins and a Ras-responsive element (B10 RRE) to analyse the signalling pathway in UVB-stimulated gene transcription in cultured keratinocytes. We demonstrate that the tumour promoters TPA and UVB use different signalling intermediates to activate different sets of Rel/NF-kappa B proteins. UVB transactivation is independent of PKC activity but dependent on tyrosine kinase activity where was TPA stimulation requires PKC but not tyrosine kinase activity. Furthermore, neither UVB- nor TPA-transactivation is mediated through p21 Ras but both stimuli are dependent on a functional Raf protein. A constitutively active Raf-1 kinase however, was unable to induce transactivation through VLTRE. Thus, Raf has an essential but permissive role in UVB activation of Rel proteins. These findings demonstrate that keratinocytes contain a novel Ras-independent pathway for induction of Rel mediated transcription.
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PMID:Ras-independent activation of Rel-family transcription factors by UVB and TPA in cultured keratinocytes. 863

In this study, we investigated the influence of the protein kinase C (PKC)-dependent system upon the ability of insulin to stimulate p21(ras).GTP loading in 3T3-L1 adipocytes. Activation of PKC by 12-0-tetradecanoylphorbol-13-acetate (TPA) did not affect the basal amount of p21(ras).GTP but significantly reduced insulin-induced increases in p21(ras).GTP. This reduction was due to inhibition of the insulin's ability to stimulate guanine nucleotide exchange activity of Sos in cells incubated with 100 nM TPA for either 30 min or 3 h. TPA had no effect on basal activity of Sos. Depletion of PKC by an 18-h incubation with TPA or inhibition by bisindolylmaleimide resulted in profound inhibition of the insulin-induced p21(ras).GTP loading. In contrast to PKC activation, removal of PKC did not influence Sos activity but resulted in a 2-fold stimulation of GTPase activating protein (GAP). This effect of PKC depletion is unique to 3T3-L1 adipocytes and was not observed in either 3T3-L1 fibroblasts or Rat-1 fibroblasts. Thus, it appears that in 3T3-L1 adipocytes, PKC has a constitutive inhibitory effect on GAP that permits insulin to activate Sos and p21(ras). Removal of this inhibitory influence activates GAP and reduces insulin-stimulated p21(ras).GTP loading.
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PMID:Interactions of protein kinase C with insulin signaling. Influence on GAP and Sos activities. 866 73

The CEF-4/9E3 cytokine gene is expressed aberrantly in chicken embryo fibroblasts (CEF) transformed by the Rous sarcoma virus. The expression of CEF-4 is dependent on both transcriptional and post-transcriptional mechanisms of regulation. The characterization of the promoter region indicated that three distinct regulatory elements corresponding to an AP-1 binding site (or TRE), a PRDII/kappaB domain, and a CAAT box are involved in the activation by pp60(v-)src. In this report we investigate the signaling pathways controlling the expression of the TRE and PRDII domain. The expression of a dominant negative mutant of p21(ras) reduced the activity of both elements. In contrast a similar mutant of c-Raf-1 affected modestly the activation dependent on the TRE but not PRDII. The stress-activated protein kinase (SAPK)/Jun N-terminal kinase (JNK) pathway was important for the activity of PRDII and the TRE but was not markedly stimulated by pp60(v-)src. The addition of calphostin C and the inhibition of protein kinase C (PKC) diminished the accumulation of the CEF-4 mRNA and reduced the activity of a TRE-controlled promoter. Likewise, the depletion of PKC by chronic treatment with phorbol esters inhibited the activation of the TRE. Rous sarcoma virus-transformed CEF treated with calphostin C were also flatter, did not display a high degree of criss-crossing, and appeared morphologically normal. Hence PKC was important for the activation of AP-1 and the morphological transformation of CEF. The constitutive expression of CEF-4 was correlated with transformation only when dependent on the TRE. This was not true for PRDII, which was the only element required for the constitutive activation to the CEF-4 promoter in nontransformed cells treated chronically with phorbol esters.
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PMID:Multiple signaling pathways control the activation of the CEF-4/9E3 cytokine gene by pp60v-src. 879 20


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