Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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During platelet secretion granule membrane glycoproteins are translocated to the plasma membrane. We report here the biochemical and immunohistochemical characterization of a panel of platelet-secretion-specific, CD62 and CD63 monoclonal antibodies (MoAb), which we raised to thrombin-activated platelets. The CD62 MoAb identify the alpha-granule membrane protein GMP-140, also designated platelet activation-dependent granule external membrane protein (PADGEM). The number of epitopes on thrombin-activated platelets ranged from 15,000 to 20,000. The CD63 MoAb recognize a 30-60 kDalton integral membrane protein of lysosomes. Due to its distinct localization, we have designated the CD63 antigen lysosome integral membrane protein, CD63 (LIMP-CD63). The number of epitopes on thrombin-activated platelets ranged from 9000 to 11,000. Expression of GMP-140, a member of the Selectin family (also referred as the LEC-CAM family) of adhesion molecules, and LIMP-CD63 was examined on human spleen, thymus and lymph node by immunohistochemistry. Both GMP-140 and LIMP-CD63 showed a wide distribution in lymphoid tissues; vascular endothelial cells and tissue compartments that were readily accessible to blood-borne components were uniformly positive for GMP-140 and LIMP-CD63. Furthermore, LIMP-CD63 was expressed in polymorphonuclear granulocytes and macrophages.
Virchows Arch B Cell Pathol Incl Mol Pathol 1991
PMID:Biochemical and immunohistochemical characteristics of CD62 and CD63 monoclonal antibodies. Expression of GMP-140 and LIMP-CD63 (CD63 antigen) in human lymphoid tissues. 172 56

1. Dimethylsulfoxide-induced differentiated neuroblastoma express high levels of membrane 21 to 23-kDa carboxyl methylated proteins. Relationships among methylation, isoprenylation, and GTP binding in these proteins were investigated. Protein carboxyl methylation, protein isoprenylation, and [alpha-32P]GTP binding were determined in the electrophoretically separated proteins of cells labeled with the methylation precursor [methyl-3H]methionine or with an isoprenoid precursor [3H]mevalonate. 2. A broad band of GTP-binding proteins, which overlaps with the methylated 21 to 23-kDa proteins, was detected in [alpha-32P]GTP blot overlay assays. This band of proteins was separated in two-dimensional gels into nine methylated proteins, of which four bound GTP. 3. The carboxyl-methylated 21 to 23-kDa proteins incorporated [3H]mevalonate metabolites with characteristics of protein isoprenylation. The label was not removed by organic solvents or destroyed by hydroxylamine. Incorporation of radioactivity from [3H]mevalonate was enhanced when endogenous levels of mevalonate were reduced by lovastatin, an inhibitor of mevalonate synthesis. Lovastatin blocked methylation of the 21 to 23-kDa proteins as well (greater than 70%). 4. Methylthioadenosine, a methylation inhibitor, inhibited methylation of these proteins (greater than 80%) but did not affect their labeling by [3H]mevalonate. The results suggest that methylation of the 21 to 23-kDa proteins depends on, and is subsequent to, isoprenylation. The sequence of events may be similar to that known in ras proteins, i.e., carboxyl methylation of a C-terminal cysteine that is isoprenylated. 5. Lovastatin reduced the level of small GTP-binding proteins in the membranes and increased GTP binding in the cytosol. Methylthioadensoine blocked methylation without affecting GTP binding. 6. Thus, isoprenylation appears to precede methylation and to be important for membrane association, while methylation is not required for GTP binding or membrane association. The role of methylation remains to be determined but might be related to specific interactions of the small GTP-binding proteins with other proteins.
Cell Mol Neurobiol 1991 Aug
PMID:Relationship among methylation, isoprenylation, and GTP binding in 21- to 23-kDa proteins of neuroblastoma. 175 64

To evaluate ras-mediated signal transduction, an alkaline phosphatase gene (SEAP) was placed under the control of the ras-inducible phorbol ester response element (TRE) in murine fibroblasts (TRE-SEAP cells). The Kirsten ras gene was placed under the control of the glucocorticoid-inducible mouse mammary tumor virus promoter and introduced into the TRE-SEAP cells. Dexamethasone increased ras expression in the TRE-SEAP cells carrying the Kirsten ras gene and stimulated SEAP activity 25-fold. Lavostatin blocked dexamethasone induction of SEAP activity (50% inhibitory concentration, 0.5 microM) but did not affect phorbol ester-induced SEAP activity in the same cells. Lovastatin also did not block forskolin induction of SEAP activity in cells expressing SEAP under the control of the cyclic AMP response element.
Mol Cell Biol 1991 Apr
PMID:Lovastatin selectively inhibits ras activation of the 12-O-tetradecanoylphorbol-13-acetate response element in mammalian cells. 200 14

The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase was characterized in cockroach corpora allata which produce insect juvenile hormone III (methyl-(10R)10,11-epoxy-3,7,11-tri-methyl-2E,6E-dodecadienoate ). HMG-CoA reductase is a microsomal enzyme dependent on NADPH and dithiothreitol (or glutathione) for activity. The enzyme selectively reduced (3S)-HMG-CoA to (3R)-mevalonate with an apparent KM of 7.6 microM. Mevinolin was a competitive inhibitor of HMG-CoA reductase with a KI of 2.4 nM. No evidence for a modulation of enzyme activity by phosphorylation was obtained. Levels of HMG-CoA reductase were not altered after incubation of the corpora allata with either mevinolin (to decrease isoprenoid flux) or with mevalonate or farnesol (to increase isoprenoid flux). Split pairs of corpora allata were used to compare JH III synthetic activity with HMG-CoA reductase activity during the cycle of JH III synthesis that controls vitellogenesis and oocyte growth in adult females. Both activities changed over 10-fold and peaked on day 5 after emergence/mating, but JH III synthesis did not parallel HMG-CoA reductase activity precisely thereafter. The half-life of HMG-CoA reductase measured in the presence of cycloheximide was significantly different between low and high activity glands and was not related to the half-life of JH III synthesis. The results suggest that HMG-CoA reductase should not be considered 'the rate-limiting enzyme' in juvenile hormone synthesis by Diploptera punctata corpora allata.
Mol Cell Endocrinol 1987 Oct
PMID:Characterization and regulation of HMG-CoA reductase during a cycle of juvenile hormone synthesis. 366 99

A fungal metabolite, ML236B (Compactin), isolated from Penicillium citrinum, is a specific inhibitor of 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A reductase (EC 1.1.1.34). Three ML236B-resistant (ML236Br) mutants, MF-1, MF-2, and MF-3, were isolated from V79 after N-methyl-N'-nitro-N-nitrosoguanidine mutagenesis. The fluctuation test showed 2.2 X 10(-6) mutants per cell per generation of a spontaneous mutation frequency of ML236Br clones. These ML236Br clones showed a four- to fivefold-higher resistance to the drug than did their parental V79. Radioactive acetate, but not mevalonate, incorporation into the sterol fraction increased about 10-fold in ML236Br clones in comparison with that in V79. The cellular level of HMG-coenzyme A reductase in three ML236Br mutants was found to be a few-fold higher than that of V79 when cultured in the presence of lipoproteins. The 125I-labeled low-density lipoprotein-binding assay showed binding activity in three ML236Br clones comparable to that of the parental V79 cells. By contrast, an internalization assay of 125I-labeled low-density lipoprotein into the cells showed significantly reduced activity in three ML236Br clones in comparison with V79.
Mol Cell Biol 1982 Nov
PMID:Chinese hamster cell mutant resistant to ML236B (Compactin) is defective in endocytosis of low-density lipo-protein. 716 16

Alcohol metabolism may result in oxidant stress and free radical injury through a variety of mechanisms. Lovastatin may also produce oxidant stress by reducing levels of an endogenous antioxidant, coenzyme Q (CoQ). The separate and combined effects of ethanol, 20 EN% in a total liquid diet, and lovastatin, 67 mg/kg diet, on alpha-tocopherol, retinol palmitate, CoQ9 and thiobarbituric acid reactive (TBAR) material in liver from rats were determined. The effect of exogenous CoQ10 on these treatment groups was also determined. Food consumption, weight gain, liver lipid and TBAR material were similar between treatment groups. Compared to control animals, ethanol reduced retinol palmitate significantly, from 143 to 90 micrograms/g wet weight. Lovastatin had no effect on retinal palmitate nor did it act additively with ethanol. Ethanol decreased liver alpha-tocopherol from 28 to 12 micrograms/g wet weight and lovastatin diminished it to 12 micrograms; no additive effect was evident. Ethanol had no effect, but lovastatin decreased CoQ9 from 83 to 55 micrograms/g wet weight. Supplementation with CoQ10 did not modulate the effect of ethanol on retinal palmitate, but it did reverse the effect of lovastatin on CoQ9. Supplementary CoQ10 did not alter control levels of alpha-tocopherol, but it appeared to reverse most of the decrease in alpha-tocopherol attributable to ethanol or lovastatin separately. It only partially reversed the effect of ethanol and lovastatin combined on alpha-tocopherol, however. As expected, lovastatin had no effect on CoQ10 levels in supplemented animals. Ethanol, either separately or in combination with lovastatin, diminished liver stores of CoQ10 by almost 40%. We conclude that 20 EN% ethanol given in a liquid diet for 5 weeks is sufficient to lower retinol palmitate and that lovastatin reduces CoQ9. Both diminish alpha-tocopherol, an effect largely overcome by CoQ10 supplementation with either drug alone, but not with the combination. Since many individuals chronically consume the levels of ethanol represented by this experiment, and since a certain number of those also take lovastatin, further research into the possible clinical significance of these observations is warranted.
Mol Aspects Med 1994
PMID:Effects of ethanol, lovastatin and coenzyme Q10 treatment on antioxidants and TBA reactive material in liver of rats. 775 31

Unprocessed p21 Ras proteins microinjected into Xenopus oocytes were radiolabeled by coinjected [3H]farnesyl pyrophosphate, a direct farnesyl donor substrate for all known mammalian farnesyltransferases. Mevinolin, an inhibitor of HMG CoA reductase which reduces the levels of mevalonate and thus farnesyl pyrophosphate, blocked oncogenic H-Rasva112 induced germinal vesicle breakdown in oocytes. This mevinolin caused block was completely reversed by co-injected farnesyl pyrophosphate. The putative farnesyltransferase in Xenopus oocytes was identified to be similar to those found in mammalian cells in that it requires an intact CAAX box motif in addition to the conserved cysteine residue at the fourth position from the C-terminus of Ras proteins for its farnesylating activity. Peptide inhibitors of farnesyltransferase such as CVIM and TKCVIM were shown to inhibit farnesylation of microinjected Ras proteins thereby blocking its function namely the induction of oocyte maturation. These results demonstrate that Xenopus oocytes process bacterially produced mammalian Ras proteins in a manner similar to, if not identical with that in mammalian cells, thus validating the continued use of the Xenopus oocyte system for unraveling the functions of Ras proteins. Furthermore, our results indicate that the oocyte system may be a useful in vivo model for studying the farnesylation of human Ras proteins, its regulation, and the effects of farnesyltransferase inhibitors.
Cell Mol Biol Res 1994
PMID:Farnesylation of p21 Ras proteins in Xenopus oocytes. 786 32

Selenocysteine tRNA[Ser]Sec isoacceptors contain the modified nucleotide i6A immediately 3' to the anticodon. Because synthesis of i6A is expected to be inhibited by lovastatin, the status of tRNA[Ser]Sec isoacceptors was examined in human breast carcinoma cells. As part of the initial characterization of these cells, it was determined that an adriamycin resistant derivative of the MCF-7 cell line exhibited a dramatic increase in the sensitivity to the killing effects of lovastatin relative to the parental MCF-7 cells. When MCF-7Adr cells were incubated with high levels of lovastatin, there was a dramatic perturbation in the distribution of isoacceptors within the selenocysteine tRNA population. Lovastatin may therefore be a useful reagent for both the study of differential killing of drug-resistant tumor cells and selenoprotein biosynthesis.
Biochem Mol Biol Int 1996 Feb
PMID:Lovastatin effects on human breast carcinoma cells. Differential toxicity of an adriamycin-resistant derivative and influence on selenocysteine tRNAS. 885 May 30

Farnesylation of the activated ras oncogene product by protein farnesyltransferase (FTase) is a critical step for its oncogenic function. Because squalene synthase and FTase recruit farnesyl pyrophosphate as a common substrate, we modified squalene synthase (SS) inhibitors to develop FTase inhibitors. Among the compounds tested, a novel FTase inhibitor termed J-104,871 inhibited rat brain FTase with an IC50 of 3.9 nM in the presence of 0.6 microM farnesyl pyrophosphate (FPP), whereas it scarcely inhibited rat brain protein geranylgeranyltransferase-I or SS. The in vitro inhibition of rat brain FTase by J-104,871 depends on the FPP concentration but not on the concentration of Ras peptide. Thus, in vitro studies strongly suggest that J-series compounds have an FPP-competitive nature. J-104,871 also inhibited Ras processing in activated H-ras-transformed NIH3T3 cells with an IC50 value of 3.1 microM. We tested the effects of lovastatin and zaragozic acid A, which modify cellular FPP levels, on Ras processing of J-104,871. Lovastatin, a hepatic hydroxymenthyl coenzyme A reductase inhibitor that reduced the cellular FPP pool, increased the activity of J-104,871, whereas 3 microM zaragozic acid A, an SS inhibitor that raised the FPP level, completely abrogated the activity of J-104,871 even at 100 microM. These results suggest that J-104,871 inhibits FTase in an FPP-competitive manner in whole cells as well as in the in vitro system. Furthermore, J-104,871 suppressed tumor growth in nude mice transplanted with activated H-ras-transformed NIH3T3 cells.
Mol Pharmacol 1998 Jul
PMID:J-104,871, a novel farnesyltransferase inhibitor, blocks Ras farnesylation in vivo in a farnesyl pyrophosphate-competitive manner. 965 83

Morbidity, mortality and the incidence of myocardial revascularisation procedures can be reduced by simvastatin, an inhibitor of the HMG-CoA reductase (EC 1.1.1.34). It was hypothesised that inhibition of isoprenylation of signalling proteins by HMG-CoA reductase inhibitors (vastatins), especially of the p21ras proteins could be causative for suppression of vascular smooth muscle cell (SMC) proliferation. The primary pharmacological mechanism of vastatins on human vascular SMC still remains unexplained. To analyse the influence of vastatins, SMC grown in presence of endothelial cell growth supplement (ECGS) were exposed to different concentrations of lovastatin. At 10 microM concentration, inhibition of SMC proliferation was associated with induction of apoptosis in a large fraction of cells as at the 1 microM level apoptosis was induced only in a minority of SMC. Protein phosphorylation on tyrosine, serine and threonine residues demonstrated no differences to untreated controls. Lovastatin induced arrest of cells in G0/G1 phase of the cell cycle and DNA synthesis was reduced. Western blot analysis demonstrated a significant induction of p21WAF1/Cip1 protein expression. This led to strong inhibition of cyclin dependent kinases (cdks) resulting in a cell cycle arrest. Our study provides evidence for a pharmacological explanation for the inhibition of ECGS-driven proliferation of human SMC by lovastatin.
Int J Mol Med 1999 Jan
PMID:Lovastatin induces p21WAF1/Cip1 in human vascular smooth muscle cells: influence on protein phosphorylation, cell cycle, induction of apoptosis, and growth inhibition. 986 87


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