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)

A monoclonal antibody MEM-43 was prepared, which recognizes an antigen expressed on all peripheral blood leucocytes, on erythrocytes and several cell lines, but is absent from U937, Nalm-6, Daudi and Raji cell lines. The antigen isolated by immunoaffinity chromatography from several cell lines is an 18,000-25,000 mol. wt glycoprotein. An apparently identical antigen isolated from erythrocytes binds to several lectins and has a 14,000 mol. wt polypeptide backbone, modified by an endoglycosidase F-sensitive carbohydrate moiety. The epitope recognized is reduction-sensitive. The sequence of N-terminal 17 amino acid residues was determined; five out of six N-terminal amino acids are identical to those found at the N-terminus of the mouse lymphocyte surface antigen Ly-6C. The antigen is completely released from the cell surface after treatment with phosphatidylinositol-specific phospholipase C.
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PMID:Characterization of a broadly expressed human leucocyte surface antigen MEM-43 anchored in membrane through phosphatidylinositol. 291 59

N mustard resistant Walker cells exhibit the same frequency of DNA interstrand cross-links and the same rate of cross-link removal as the sensitive parental line. Employing cytostatically active concentrations of chlorambucil covalently bound to polyethyleneimine, the extent of DNA cross-linking is reduced to levels observed in the presence of nontoxic concentrations of free chlorambucil. It is concluded, therefore, that DNA cross-links alone are not sufficient to explain the inhibition of cell multiplication by alkylating agents and that additional mechanisms have to be considered. Evidence for an interference of alkylating agents with several enzymes of the plasma membrane is presented. An inhibition by N mustard of the furosemide-sensitive Na+/K+/Cl- -cotransport and the Na+/H+-antiport is described in greater detail. Considering the fact that the enzymes which are affected by alkylating agents are controlled by growth factors it was investigated whether a synergism between inhibitors of early growth-factor-controlled reactions and alkylating agents is to be seen. It is demonstrated that mepacrine, an inhibitor of phospholipase C, and the calmodulin binding drugs, chlorpromazine and flunarizine, amplify the action of N mustard.
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PMID:Plasma membrane as target of alkylating agents. 294 Aug 19

Radioiodinated phospholipid ethers have shown the remarkable ability to selectively accumulate in a variety of animal tumors as well as in human tumor xenografts. It has been suggested that this tumor avidity may arise as a consequence of metabolic differences between tumor and corresponding normal tissue. One such compound, 1-O-[12-(m-iodophenyl)dodecyl]-2-O-methyl-rac-glycero-3-phosphocholine (NM-294), contains a chiral center at the sn-2 position. The unnatural S- and natural R-enantiomers (4 and 5, respectively) of NM-294 were synthesized in order to provide further information on the mechanism(s) responsible for the tumor avidity of phospholipid ethers. In vitro cytotoxicity studies demonstrated a lack of stereospecificity. Biodistribution studies in rats bearing the Walker 256 tumor demonstrated the S- and R-isomers to have similar tissue uptake at 24 and 48 h after administration. Tumor-to-blood ratios at 24 h were 11.1 and 11.0 for the S- and R-isomers, respectively. In addition, gamma-camera scintigrams of tumor-bearing rats at various time points after iv administration of the S- and R-isomers did not show any qualitative differences in the distribution of radioactivity. Prior studies have shown that rac-NM-294 was not a substrate for phosphatidylcholine specific phospholipase C, but was a substrate for two forms of phospholipase D (PLD). Therefore, metabolism studies with 4 and 5 with various forms of PLD were performed. PLD from cabbage demonstrated a degree of stereoselectivity. In the presence of 1% ethanol, the R-isomer was metabolized to the greatest extent, followed by rac-NM-294 and the S-isomer. PLD isolated from Streptomyces chromofuscus failed to demonstrate any stereoselectivity. The results suggest that the mechanism(s) of retention of these compounds in tumors may not involve a highly stereoselective component.
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PMID:Synthesis and biological evaluation of radioiodinated phospholipid ether stereoisomers. 763 78

Previous study has shown that insulin secretion in response to a glucose stimulus (16.7 mM) is reduced in islets isolated from Walker 256 tumor-bearing rats compared with controls. The ultrastructure, 45Ca2+ and 86Rb+ fractional outflow rate, phosphoinositide hydrolysis, and [U-14C]glucose decarboxylation were examined in islets isolated from tumor-bearing and control rats. The general morphological features of the islets from the control and experimental groups were very similar. The 86Rb+ fractional outflow rate was not changed, whereas the 45Ca2+ fractional outflow rate, [U-14C]glucose decarboxylation, and phosphoinositide metabolism were markedly reduced in islets from tumor-bearing rats. The changes in 45Ca2+ fractional outflow rate in islets from tumor-bearing rats were not due to impaired functioning of voltage-dependent calcium channels. By perifusing the islets in the presence of high potassium concentration, evidence was obtained that phospholipase C from islets from tumor-bearing rats reduced response to calcium. To further examine the mechanism involved in the impairment of insulin secretion by islets from tumor-bearing rats, islets isolated from normal rats were perifused after preincubation in the presence of serum from tumor-bearing rats. The results suggest that a thermolabile circulating factor is partially responsible for the changes described in islets isolated from Walker 256 tumor-bearing rats.
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PMID:Impairment of insulin secretion in pancreatic islets isolated from Walker 256 tumor-bearing rats. 884 9

Parathyroid hormone (PTH)-related protein (PTHrP) is the main factor responsible for humoral hypercalcemia of malignancy. Both PTH and PTHrP bind to the common type I PTH/PTHrP receptor (PTHR), thereby activating phospholipase C and adenylate cyclase through various G proteins, in bone and renal cells. However, various normal and transformed cell types, including hypercalcemic Walker 256 (W256) tumor cells, do not produce cAMP after PTHrP stimulation. We characterized the PTHrP receptor and the signaling mechanism upon its activation in the latter cells. Scatchard analysis of PTHrP-binding data in W256 tumor cells revealed the presence of high affinity binding sites with an apparent K(d) of 17 nM, and a density of 90 000 sites/cell. In addition, W256 tumor cells immunostained with an anti-PTHR antibody, recognizing its extracellular domain. Furthermore, reverse transcription followed by PCR, using primers amplifying two different regions in the PTHR cDNA corresponding to the N- and C-terminal domains, yielded products from W256 tumor cell RNA which were identical to the corresponding products obtained from rat kidney RNA. Consistent with our previous findings on cAMP production, 1 microM PTHrP(1-34), in contrast to 10 microg/ml cholera toxin or 1 microM isoproterenol, failed to affect protein kinase A activity in W256 tumor cells. However, in these cells we found a functional PTHR coupling to G(alpha)(q/11), whose presence was demonstrated in these tumor cell membranes by Western blot analysis. Our findings indicate that W256 tumor cells express the PTHR, which seems to be coupled to G(alpha)(q/11). Taken together with previous data, these results support the hypothesis that a switch from the cAMP pathway to the phospholipase C-intracellular calcium pathway, associated with PTHR activation, occurs in malignant cells.
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PMID:Characterization of parathyroid hormone/parathyroid hormone-related protein receptor and signaling in hypercalcemic Walker 256 tumor cells. 1085 78

Telokin, a 17 kDa smooth muscle specific protein, consists of the C-terminal domain of MLCK, is phosphorylated by PKA and PKG at Ser13 in vivo (Wu et al. (1998) J Biol Chem 273: 11362-11369; Walker et al. (2001) J. Biol Chem 276: 24519-24524) and is proposed to induce Ca2+-desensitization through activation of myosin phosphatase (Wu et al. (1998) J. Biol Chem 273: 11362-11369). Telokin is reported to be highly expressed in phasic with only trace amounts in tonic smooth muscle. In alpha-toxin permeabilized femoral artery, 5 microM 8-Br-cGMP induced a two-fold increase in telokin phosphorylation and a maximal 30% relaxation of Ca2+-activated force compared to a 90% relaxation in phasic ileum muscle consistent with the relative amounts of telokin expressed in ileum, 27+/-4.6 microM SEM compared to 6+/-1.7 microM SEM, in femoral artery. Recombinant Wt telokin and the phospho-telokin mutant, S13D relaxed telokin-depleted femoral artery, by 38+/-8% SEM and 60+/-20% SEM, respectively. 8-Br-cGMP increased the rate and decreased the amplitude of force development initiated by photolysis of caged ATP in alpha-toxin permeabilized ileum and femoral artery smooth muscle, consistent with a cGMP-induced increase in phosphatase activity. Similarly, in telokin depleted ileum, recombinant S13D mutant telokin significantly increased the rate (0.08+/-0.01 s-1 vs. 014+/-0.02 s-1) and decreased force amplitude. In conclusion, our data support a role for telokin in cyclic nucleotide-induced relaxation of not only phasic, but also tonic smooth muscle and that this relaxation is mediated by activation of myosin phosphatase activity leading to a decrease in myosin light chain phosphorylation.
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PMID:Telokin mediates Ca2+-desensitization through activation of myosin phosphatase in phasic and tonic smooth muscle. 1575 Aug 50