Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using a model of cycloheximide (CHI)-induced expression of nuclear oncogens, a comparative study of metabolism of the major lipid classes in rat liver nuclei and cells was carried out. A short-term activation of sphingomyelinase which preceded on a time scale the maximal accumulation of c-fos and c-myc transcripts was observed both in the cells and in the nuclei. In contrast with the whole cell, the level of phospholipase C activity in the nuclei did not change under conditions of oncogene activation. It was found that the maximal expression of nuclear oncogens coincided in time with cyclic changes in the content of practically all phospholipids and neutral lipids with simultaneous activation of their synthesis both in the cells and in the nuclei. However, in the nuclei the sphingomyelin metabolism activation was predominant. It is concluded that in the nucleus sphingomyelin and its metabolites may influence oncogene expression via nuclear protein kinase C.
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PMID:[Comparison of lipid metabolism in rat liver cells and nuclei during cycloheximide-induced superinduction of nuclear oncogenes]. 174 15

Endothelin (ET)-1, an endothelium-derived vasoactive polypeptide encoded in the human genome, is the most potent vasoconstrictor identified to date. In addition to its acute role in modulating vascular smooth muscle tone, ET-1 also plays a critical role in the long-term control of cellular growth within the vasculature and thus, modulates the chronic remodeling of the vascular tree. In order to produce such a diverse range of biological responses, this peptide is able to activate numerous distinct effector systems including phospholipase C, phospholipase D, phospholipase A2, adenylate and guanylate cyclases and numerous cytosolic/nuclear protein kinases. These actions, mediated via an interaction with two major subtypes of cell surface seven-transmembrane receptors (ET(A) and ET(B)), are coupled to their effector systems by several distinct types of guanine nucleotide regulatory proteins (both inhibitory and stimulatory G proteins). This review describes such intercations and how distinct pharmacological agents have been used to identify the diverse signaling mechanisms utilized by the ET isopeptides.
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PMID:Signal transduction mechanisms mediating the vascular actions of endothelin. 922 97

It has recently been reported (T. Shimizu et al., J. Biol. Chem., 273: 8669-8674, 1998) that the pro-apoptotic drug, camptothecin, an inhibitor of topoisomerase I, induces a protein kinase C-alpha-mediated phosphorylation of lamin B in HL-60 cells, which precedes both degradation of lamin B and fragmentation of DNA. In this paper, we report that, in HL-60 cells exposed to camptothecin, there is a rapid and sustained increase of nuclear protein kinase C-alpha activity that is due to an increase in the amount of protein kinase C-alpha present in the nucleus. The enhancement of nuclear kinase C activity is preceded by an increase in the mass of nuclear diacylglycerol. As demonstrated by its sensitivity to propranolol, the nuclear diacylglycerol mass increase is due to the activation of a phospholipase D. Indeed, inhibitors of neither phosphatidylcholine-specific phospholipase C nor phosphoinositide-specific phospholipase C blocked the rise in nuclear diacylglycerol. In vitro assays also demonstrated the activation of a nuclear phospholipase D, but not of a phosphoinositide-specific phospholipase C, after treatment with camptothecin. Propranolol was also able to block the rise in nuclear protein kinase C-alpha activity, thus suggesting that the increase in diacylglycerol mass is important for the activation of the kinase at the nuclear level. Moreover, propranolol was capable of drastically reducing the number of HL-60 cells that underwent apoptosis after treatment with camptothecin. Our results show the activation during apoptosis of a phospholipase D-mediated signaling pathway operating at the nuclear level. This pathway may represent an attractive therapeutic target for the modulation of apoptotic events in human disease.
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PMID:The pro-apoptotic drug camptothecin stimulates phospholipase D activity and diacylglycerol production in the nucleus of HL-60 human promyelocytic leukemia cells. 1046 92

We present the first evidence for a fast activation of the nuclear protein poly(ADP-ribose) polymerase (PARP) by signals evoked in the cell membrane, constituting a novel mode of signaling to the cell nucleus. PARP, an abundant, highly conserved, chromatin-bound protein found only in eukaryotes, exclusively catalyzes polyADP-ribosylation of DNA-binding proteins, thereby modulating their activity. Activation of PARP, reportedly induced by formation of DNA breaks, is involved in DNA transcription, replication, and repair. Our findings demonstrate an alternative mechanism: a fast activation of PARP, evoked by inositol 1,4,5,-trisphosphate-Ca(2+) mobilization, that does not involve DNA breaks. These findings identify PARP as a novel downstream target of phospholipase C, and unveil a novel fast signal-induced modification of DNA-binding proteins by polyADP-ribosylation.
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PMID:A fast signal-induced activation of Poly(ADP-ribose) polymerase: a novel downstream target of phospholipase c. 1090 73

The Saccharomyces cerevisiae PLC1 gene encodes a homolog of the delta isoform of mammalian phosphoinositide-specific phospholipase C. Cells deleted for PLC1 ( plc1Delta) are viable, but display several phenotypes, including osmotic, temperature, and nocodazole sensitivity. We have used a two-hybrid screen to identify Plc1p-interacting proteins. One of the interacting proteins found was Sgd1p, a recently identified, essential, nuclear protein. The SGD1 gene was originally cloned by complementation of an osmostress-sensitive mutant. The Plc1p-Sgd1p interaction was confirmed biochemically by affinity chromatography. SGD1 interacts genetically with both PLC1 and HOG1 (which encodes an osmosensing mitogen-activated protein kinase). Overexpression of Sgd1p suppresses the temperature sensitivity of cells bearing the plc1-4 allele, and the double mutant strain plc1Delta sgd1-1 displays enhanced temperature and nocodazole sensitivity. The plc1Delta hog1Delta strain displays increased osmosensitivity, and has a synthetic defect in glycerol synthesis and the expression of GPD1 (which encodes the enzyme glycerol 3-phosphate dehydrogenase that is involved in glycerol biosynthesis), suggesting that Plc1p and Hog1p function in independent pathways. The hog1Delta sgd1-1 double mutant displays enhanced osmosensitivity relative to that of either single mutant. The triple mutant plc1Delta hog1Delta sgd1-1 is inviable, while the plc1Delta hog1Delta sgd1-2 strain grows extremely slowly and is more osmosensitive than the plc1Delta hog1Delta or hog1Delta sgd1-2 strain. These results are consistent with a model in which Plc1p and Hog1p function in parallel pathways affecting osmoregulation, and signals from both these pathways converge, at least partly, on Sgd1p.
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PMID:Phospholipase C interacts with Sgd1p and is required for expression of GPD1 and osmoresistance in Saccharomyces cerevisiae. 1207 33

The t(2;5) chromosomal translocation occurs in anaplastic large-cell lymphoma arising from activated T lymphocytes. This genomic rearrangement generates the nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) oncoprotein that is a chimeric protein consisting of parts of the nuclear protein NPM and ALK receptor protein-tyrosine kinase. We used yeast two-hybrid screening to identify an adaptor protein Suc1-associated neurotrophic factor-induced tyrosine-phosphorylated target (SNT)-2 as a new partner that interacted with the cytoplasmic domain of ALK. Immunoprecipitation assay revealed that SNT-1 and SNT-2 interacted with NPM-ALK and kinase-negative NPM-ALK mutant. Y156, Y567 and a 19-amino-acid sequence (aa 631-649) of NPM-ALK were essential for this interaction. The interaction through Y156 and Y567 was dependent on phosphorylation of these tyrosines, whereas the interaction through the 19-amino-acid sequence was independent of phosphorylation. NPM-ALK mutant protein mutated at these three binding sites showed significantly reduced transforming activity. This transformation-defective NPM-ALK mutant still interacted with signal transducing proteins such as phospholipase C-gamma and phosphatidylinositol 3-kinase, which were previously reported to be relevant to NPM-ALK-dependent tumorigenesis. These observations indicate that the three SNT-binding sites of NPM-ALK are important for its transforming activity. This raises a possibility that SNT family proteins play significant roles in cellular transformation triggered by NPM-ALK, which though remains to be verified.
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PMID:Identification of multiple SNT-binding sites on NPM-ALK oncoprotein and their involvement in cell transformation. 1708 10

Hypoxia is shown to regulate the stress hormone epinephrine through its biosynthesis by phenylethanolamine N-methyltransferase (PNMT) via PNMT gene activation and transcription factors Egr-1 and Sp1 in adrenal medulla-derived PC12 cells. Moderate hypoxia (5% oxygen) markedly stimulates PNMT promoter-driven luciferase activity in the cells. Hypoxia increases Egr-1 and Sp1 mRNA and nuclear protein content and Egr-1 and Sp1 protein-DNA binding complex formation. Subsequent to transcription factor induction, endogenous PNMT mRNA and protein also increase. Egr-1 and Sp1 binding site inactivation or Egr-1 and Sp1 siRNA inhibit PNMT promoter stimulation by hypoxia. Hypoxia elevates protein kinase A (PKA), phospholipase C (PLC), phosphoinositide 3-kinase, protein kinase C, ERK1/2 mitogen-activated protein kinase and p38 mitogen-activated protein kinase expression while selective inhibitors of these signaling enzymes abrogate hypoxic induction of the PNMT promoter and the rise in Egr-1, Sp1 and PNMT mRNA and protein. PC12 cells lacking PKA or PLCgamma-1 show significant reduction in PNMT promoter activation by hypoxia. Signaling inhibitors do not affect these responses or reduce hypoxic induction of the PNMT promoter to a lesser extent. Findings suggest that Egr-1 and Sp1 through synergistic interaction are critical transcriptional activators for hypoxic stress-regulated adrenergic function controlled via cAMP/PKA and PLC signaling. Identification of Sp1 as a mediator of hypoxia-induced transcriptional activation of PNMT has not been previously been shown. The effects of hypoxia on PNMT and thereby epinephrine may have important ramifications for the stress hormone epinephrine, its ability to regulate behavioral and physiological processes associated with stress and stress-elicited illness.
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PMID:Hypoxia and adrenergic function: molecular mechanisms related to Egr-1 and Sp1 activation. 2065 92