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)

Angiotensin II (AngII) induces cardiac hypertrophy through activating a variety of protein kinases. In this study, to understand how cardiac hypertrophy develops, we examined AngII-evoked signal transduction pathways leading to the activation of extracellular signal-regulated protein kinases (ERKs), which are reportedly critical for the development of cardiac hypertrophy, in cultured cardiac myocytes isolated from neonatal rats. Inhibition of protein kinase C (PKC) with calphostin C or down-regulation of PKC by pretreatment with a phorbol ester for 24 h abolished AngII-induced activation of Raf-1 and ERKs, and addition of a phorbol ester conversely induced a marked increase in the activities of Raf-1 and ERKs. Pretreatment with two chemically and mechanistically dissimilar tyrosine kinase inhibitors, genistein and tyrphostin, did not attenuate AngII-induced activation of ERKs. In contrast, genistein strongly blocked insulin-induced ERK activation in cardiac myocytes. Although pretreatment with manumycin, a Ras farnesyltransferase inhibitor, or overexpression of a dominant-negative mutant of Ras inhibited insulin-induced ERK activation, neither affected AngII-induced activation of ERKs. Overexpression of a dominant-negative mutant of Raf-1 completely suppressed ERK2 activation by AngII, endothelin-1, and insulin. These results suggest that PKC and Raf-1, but not tyrosine kinases or Ras, are critical for AngII-induced activation of ERKs in cardiac myocytes.
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PMID:Protein kinase C, but not tyrosine kinases or Ras, plays a critical role in angiotensin II-induced activation of Raf-1 kinase and extracellular signal-regulated protein kinases in cardiac myocytes. 896 27

There is at present, much optimism about the possibility of finding selective anticancer drugs that will eliminate the cytotoxic side effects associated with conventional cancer chemotherapy. This hope is based on uncovering many novel molecular targets that are 'cancer-specific', which will allow the targeting of cancer cells while normal cells are spared. Thus far, encouraging results have been obtained with several of these novel agents at the preclinical level, and clinical trials have begun. These targets are involved at one level or more in tumor biology, including tumor cell proliferation, angiogenesis and metastasis. Novel targets for which advances are being made include the following: growth factor receptor tyrosine kinases such as the epidermal growth factor receptor and HER-2/neu (proliferation); the vascular endothelial growth factor receptor and the basic fibroblast growth factor receptor (angiogenesis); the oncogenic GTP-binding protein Ras (especially agents targeting Ras farnesylation, farnesyltransferase inhibitors) (proliferation); protein kinase C (proliferation and drug resistance); cyclin-dependent kinases (proliferation); and matrix metalloproteinases and angiogenin (angiogenesis and metastasis). Less explored, but potentially useful targets include the receptor tyrosine kinase platelet-derived growth factor receptor, mitogen-activated protein kinase cascade oncogenes such as Raf-1 and mitogen-activated protein kinase kinase, cell adhesion molecules such as integrins, anti-apoptosis proteins such as Bcl-2, MDM2 and survivin, and the cell life-span target telomerase.
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PMID:Novel anticancer drug discovery. 1041 54

To search for the signaling pathway critical for tumor invasion, we examined the effects of dominant negative ras (S17N ras) expression on the activation of matrix metalloproteinase-2 (MMP-2) in src-transformed 3Y1, SR3Y1, under the control of conditionally inducible promoter. In SR3Y1 clones transfected with S17N ras, augmented secretion and proteolytic activation of MMP-2 were dramatically suppressed by S17N Ras expression, while tyrosine phosphorylation of cellular proteins was not suppressed. We found that invasiveness of SR3Y1 cells assayed by the modified Boyden Chamber method was strongly suppressed by S17N Ras expression. In contrast, cell morphology reverted partially and glucose uptake remained unchanged by S17N Ras expression. In addition, treatment of SR3Y1 with manumycin A, a potent inhibitor of Ras farnesyltransferase, strongly suppressed both augmented secretion and proteolytic activation of MMP-2. Contrary, treatment of SR3Y1 with wortmannin or TPA showed no clear effect on MMP-2 activation. Thus, these results strongly suggest that Ras-signaling, but neither P13 kinase- nor protein kinase C-signalings, plays a critical role in activation of MMP-2 and, subsequently, in the invasiveness of src-transformed cells.
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PMID:Ras pathway is required for the activation of MMP-2 secretion and for the invasion of src-transformed 3Y1. 1059 59

The treatment of endothelial cell monolayers with phorbol 12-myristate 13-acetate (PMA), a direct protein kinase C (PKC) activator, leads to disruption of endothelial cell monolayer integrity and intercellular gap formation. Selective inhibition of PKC (with bisindolylmaleimide) and extracellular signal-regulated kinases (ERKs; with PD-98059, olomoucine, or ERK antisense oligonucleotides) significantly attenuated PMA-induced reductions in transmonolayer electrical resistance consistent with PKC- and ERK-mediated endothelial cell barrier regulation. An inhibitor of the dual-specificity ERK kinase (MEK), PD-98059, completely abolished PMA-induced ERK activation. PMA also produced significant time-dependent increases in the activity of Raf-1, a Ser/Thr kinase known to activate MEK ( approximately 6-fold increase over basal level). Similarly, PMA increased the activity of Ras, which binds and activates Raf-1 ( approximately 80% increase over basal level). The Ras inhibitor farnesyltransferase inhibitor III (100 microM for 3 h) completely abolished PMA-induced Raf-1 activation. Taken together, these data suggest that the sequential activation of Ras, Raf-1, and MEK are involved in PKC-dependent endothelial cell barrier regulation.
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PMID:Role of ras-dependent ERK activation in phorbol ester-induced endothelial cell barrier dysfunction. 1092 60

A 57-kDa protein in royal jelly (RJ) was previously shown to stimulate hepatocyte DNA synthesis and prolongs the proliferation of hepatocytes as well as increasing albumin production [Kamakura, M., Suenobu, N., and Fukushima, M. (2001) Biochem. Biophys. Res. Commun. 282, 865-874]. In this study, I investigated the signal transduction mechanisms involved in the induction of hepatocyte DNA synthesis and the promotion of cell survival by this 57-kDa protein in primary cultures of adult rat hepatocytes. Hepatocyte DNA synthesis induced by the 57-kDa protein was not influenced by several alpha- and beta-adrenoceptor antagonists, but was dose-dependently abolished by an inhibitor of a tyrosine-specific protein kinase, genistein. A phospholipase C inhibitor (U-73122) and a protein kinase C (PKC) inhibitor (sphingosine) inhibited 57-kDa protein-stimulated he-patocyte DNA synthesis, whereas a protein kinase A inhibitor (H-89) did not. The 57-kDa protein also activated PKC in rat hepatocytes. Various inhibitors of intracellular signal transduction elements (PD98059, p21 ras farnesyltransferase inhibitor, wortmannin and rapamycin) also blocked hepatocyte DNA synthesis induced by the 57-kDa protein. Furthermore, the 57-kDa protein activated mitogen-activated protein (MAP) kinase in rat hepatocytes. The activation of MAP kinase by the 57-kDa protein was inhibited by PD98059 and sphingosine. The 57-kDa protein also activated protein kinase B, which is a key regulator of cell survival. These results suggest that, like growth factors, the 57-kDa protein activates several important intracellular signaling factors involved in the stimulation of hepatocyte DNA synthesis and the protection of cells from apoptosis.
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PMID:Signal transduction mechanism leading to enhanced proliferation of primary cultured adult rat hepatocytes treated with royal jelly 57-kDa protein. 1247 93

Suppression of PKC activity can selectively induce apoptosis in cells expressing a constitutively activated p21Ras protein. We demonstrate that continued expression of p21Ras activity is required in PKC-mediated apoptosis because farnesyltransferase inhibitors abrogated the loss of viability in p21Ras-transformed cells occurring following PKC inhibition. Studies utilizing gene transfer or viral vectors demonstrate that transient expression of oncogenic p21Ras activity is sufficient for induction of apoptosis by PKC inhibition, whereas physiologic activation of p21Ras by growth factor is not sufficient to induce apoptosis. Mechanistically, the p21Ras-mediated apoptosis induced by PKC inhibition is dependent upon mitochondrial dysregulation, with a concurrent loss of mitochondrial membrane potential (psim). Cyclosporine A, which prevented the loss of psim, also inhibited HMG-induced DNA fragmentation in cells expressing an activated p21Ras. Induction of apoptosis by PKC inhibition in human tumors with oncogenic p21Ras mutations was demonstrated. Inhibition of PKC caused increased apoptosis in MIA-PaCa-2, a human pancreatic tumor line containing a mutated Ki-ras allele, when compared to HS766T, a human pancreatic tumor line with normal Ki-ras alleles. Furthermore, PKC inhibition induced apoptosis in HCT116, a human colorectal tumor line containing an oncogenic Ki-ras allele but not in a subline (Hke3) in which the mutated Ki-ras allele had been disrupted. The PKC inhibitor 1-O-hexadecyl-2-O-methyl-rac-glycerol (HMG), significantly reduced p21Ras-mediated tumor growth in vivo in a nude mouse MIA-PaCa-2 xenograft model. Collectively these studies suggest the therapeutic feasibility of targeting PKC activity in tumors expressing an activated p21Ras oncoprotein.
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PMID:Characterization of p21Ras-mediated apoptosis induced by protein kinase C inhibition and application to human tumor cell lines. 1460 30

Treatment of myelodysplastic syndrome (MDS) has been hampered by the lack of understanding of the molecular and biological abnormalities associated with this disease. Biological abnormalities may lead to typical phenotypic changes in more differentiated cells. Recent developments in the natural history and underlying molecular mechanisms of MDS and acute myeloid leukemia (AML) have identified new molecular therapeutic targets. Several new classes of drugs have shown promise in early clinical trials and may alter the standard of care of these patients. Among these new drugs are farnesyltransferase inhibitors, receptor tyrosine kinase inhibitors, protein kinase C inhibitors, and VEGF inhibitors. These agents have been tested in patients with solid tumors and hematological malignancies such as AML and MDS. Most of the studies in MDS are in early stages of development, where doses are being determined based on the experience in refractory or relapsed AML or solid tumors. Future therapies in MDS will attempt to resolve cytopenias, eliminate malignant clones and allow differentiation by attacking specific mechanisms of the disease.
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PMID:Inhibitors of signaling in myelodysplastic syndrome. 1549 98

In previous papers, we reported that ATP calcium responses in cerebellar astrocytes were strongly potentiated by preincubation with nanomolar concentrations of the diadenosine pentaphosphate Ap(5)A. However, the intracellular signaling pathway mediating this effect was not defined. We also showed that stimulation of astrocytes with the dinucleotide led to the activation of extracellular regulated kinases (ERKs). Here, we examined whether ERKs are involved in the potentiating mechanism and intracellular mechanism leading to their activation. Epidermal growth factor (EGF) exactly reproduced the potentiation displayed by the dinucleotide. Moreover, the potentiation of ATP responses by Ap(5)A and EGF was completely abolished by the MAP kinase (MEK) inhibitor U-0126, indicating that ERK activation is a required step for the potentiation event. Our data also indicated that ERK activation and the potentiation of ATP calcium responses were sensitive to the src-like kinase inhibitor herbimycin A, p21(ras) farnesyltransferase inhibitor peptide, and some PKC inhibitors. Taken together, our findings reveal that Ap(5)A triggers the potentiation of ATP calcium responses through an intracellular mechanism that is insensitive to pertussis toxin and that this potentiation requires src protein-mediated ERK activation and the participation of an atypical protein kinase C isoform activated downstream from ERK.
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PMID:Cross-talk among epidermal growth factor, Ap(5)A, and nucleotide receptors causing enhanced ATP Ca(2+) signaling involves extracellular kinase activation in cerebellar astrocytes. 1605 66

We identified dexamethasone-induced Ras protein 1 (Dexras1) as a negative regulator of protein kinase C (PKC) delta, and the consequences of this regulation have been examined for adenylyl cyclase (EC 4.6.1.1) type 2 (AC2) signaling. Dexras1 expression in human embryonic kidney 293 cells completely abolished dopamine D2 receptor-mediated potentiation of AC2 activity, which is consistent with previous reports of its ability to block receptor-mediated Gbetagamma signaling pathways. In addition, Dexras1 significantly reduced phorbol 12-myristate 13-acetate (PMA)-stimulated AC2 activity but did not alter Galpha(s)-mediated cAMP accumulation. Dexras1 seemed to inhibit PMA stimulation of AC2 by interfering with PKCdelta autophosphorylation. This effect was selective for the delta isoform because Dexras1 did not alter autophosphorylation of PKCalpha or PKCepsilon. Dexras1 disruption of PKCdelta autophosphorylation resulted in a significant blockade of PKC kinase activity as measured by [gamma-32P]ATP incorporation using a PKC-specific substrate. Moreover, Dexras1 and PKCdelta coimmunoprecipitated from whole-cell lysates. Dexras1 did not alter the membrane translocation of PKCdelta; however, the ability of Dexras1 to interfere with PKCdelta autophosphorylation was isoprenylation-dependent as determined using the farnesyltransferase inhibitor methyl {N-[2-phenyl-4-N [2(R)-amino-3-mecaptopropylamino] benzoyl]}-methionate (FTI-277) and a CAAX box-deficient Dexras1 (C277S) mutant. PMA-stimulated AC2 activity was also not affected by Dexras1 C277S. Taken as a whole, these data suggest that Dexras1 functionally interacts with PKCdelta at the cellular membrane through an isoprenylation-dependent mechanism to negatively regulate PKCdelta activity. Moreover our study suggests that Dexras1 acts to modulate the activation of AC2 in an indirect fashion by inhibiting both Gbetagamma- and PKC-stimulated AC2 activity. The current study provides a novel role for Dexras1 in signal transduction.
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PMID:Dexamethasone-induced Ras protein 1 negatively regulates protein kinase C delta: implications for adenylyl cyclase 2 signaling. 1648 24

As the most frequently mutated oncogene in human cancers, the small GTPase Ras is a logical target for anticancer drug development. Ras proteins serve as molecular switches regulating many key signaling processes, including growth-promoting pathways critical for normal cell functions that go awry in cancer. How to interfere selectively and successfully in oncogenic Ras function has proved to be surprisingly vexing. The complexity and importance of controlling correct subcellular localization supports the development of inhibitors that disrupt specific aspects of Ras membrane binding. Here, we concentrate on assays and compounds relevant to inhibiting enzymes responsible for post-translational modifications required for full processing and correct localization of Ras proteins or their targets. Common modifications include farnesylation (by farnesyltransferase, FTase) or geranylgeranylation (GGTase I), proteolysis (Rce1) and carboxymethylation (Icmt), as well as palmitoylation (PATs) and phosphorylation (PKC). We discuss history, current status and prospects of inhibitors designed to block these steps of prenyl and post-prenyl processing of Ras itself, or that appear to compete with oncogenic Ras (farnesyl-S-thiosalicylic acid, FTS) for key membrane binding sites that dictate its ability to transduce specific oncogenic signals. Recent patents focusing on GGTIs, Icmt and PATs, and on novel approaches to Ras inhibition, are emphasized.
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PMID:Inhibitors of chronically active ras: potential for treatment of human malignancies. 1828 22


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