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:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ras oncogene products (ras p21s) are 21-KDa proteins with activities of GTP binding and hydrolysis. A number of proteins homologous to ras p21 have been discovered and collectively named small molecular weight GTP-binding proteins. These proteins undergo post-translational modification with isoprenoid residues attached to cysteine in their carboxyl terminal. With this modification, they attach to cellular membranes. The biochemical activities of these proteins, i.e., GTP hydrolysis and binding, are regulated by various regulatory factors such as GDP-GTP exchange proteins and GTPase-activating proteins, but little is known about the cellular functions and physiological pathways through which they regulate these functions. Botulinum C3 ADP-ribosyltransferase, a 23-KDa exoenzyme secreted from certain strains of types C and D Clostridium botulinum, specifically ADP-ribosylates the rho family of these GTP-binding proteins. This ADP-ribosylation occurs at a specific asparagine residue in their putative effector domain, and presumably interferes with their interaction with a putative effector molecule downstream in signal transduction. C3 exoenzyme, when incubated with or microinjected into cultured cells, ADP-ribosylates a rho gene product in the cells, and causes profound cell rounding with loss of adhesion plaques and collapse of stress fiber. Microinjection of an activated mutant of rho A protein, on the contrary, induced extensive adhesion and actin assembly in cultured cells. These results suggest that the rho family of proteins are involved in morphogenesis and motility of cells via assembly and disassembly of cytoskeletal systems, and botulinum ADP-ribosyltransferase is a useful tool for clarifying the molecular mechanism of these processes.
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PMID:[ras oncogene-related small molecular weight GTP-binding protein, rho gene product and botulinum C3 ADP-ribosyltransferase]. 160 29

In bovine aortic smooth muscle, GTP-binding activity was equally distributed in the membrane and cytosol fractions. The most abundant GTP-binding proteins (G proteins) in each fraction were purified to near homogeneity and characterized. The most abundant G protein in the membrane fraction had a Mr value of about 22,000 (m22K G) as estimated on sodium dodecyl sulfate-polyacryl-amide gel electrophoresis (SDS-PAGE). m22K G and the human platelet smg p21, a ras p21 like G protein having the same effector domain as ras p21s, were eluted at the same retention time on C4 reversed-phase high performance liquid chromatography (HPLC). Moreover, m22K G was specifically recognized by an anti-smg p21 polyclonal antibody. m22K G was phosphorylated by cyclic AMP-dependent protein kinase with a stoichiometry of one phosphate/molecule of protein. The most abundant G protein in the cytosol fraction had a Mr value of about 21,000 (c21K G) as estimated on SDS-PAGE. c21K G was ADP-ribosylated by botulinum ADP-ribosyltransferase and about 0.4 mol of ADP-ribose was maximally incorporated into 1 mol of c21K G. c21K G and the bovine brain rhoA p21, another ras p21 like G protein, were eluted at the same retention time on C4 reversed-phase HPLC and migrated at the same position on two-dimensional gel electrophoresis. These results indicate that the major G proteins in the membrane and cytosol fractions of bovine aortic smooth muscle are smg p21 and rhoA p21, respectively. Possible roles of these G proteins in vascular smooth muscle are discussed.
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PMID:Small GTP-binding proteins in bovine aortic smooth muscle. 174 79

In bovine aortic smooth muscle, about 50% of total GTP-binding activity was present in the cytosol fraction. A major GTP-binding protein (G protein) with a Mr value of about 21,000 (21K G) in this fraction was purified to near homogeneity and characterized. 21K G bound maximally about 0.8 mol of [35S]guanosine 5'-(3-O-thio)triphosphate/mol of protein with a Kd value of about 20 nM. 21K G showed GTPase activity with a turnover number of about 0.007 min-1. 21K G was ADP-ribosylated by botulinum ADP-ribosyltransferase and about 0.4 mol of ADP-ribose was maximally incorporated into 1 mol of 21K G. 21K G and the bovine brain rhoA gene product (rhoA p21) were eluted at the same retention time on C4 reversed-phase high performance liquid chromatography and migrated at the same positions on two-dimensional gel electrophoresis. These results indicate that the major G protein in bovine aortic smooth muscle cytosol is rhoA p21.
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PMID:Identification of a major GTP-binding protein in bovine aortic smooth muscle cytosol as the rhoA gene product. 211 95

We have separated multiple GTP-binding proteins (G proteins) having Mr values of about 20,000 (small Mr G proteins) from bovine brain membranes, purified to near homogeneity and characterized two novel G proteins designated as smg p25A and smg p21, the c-Ki-ras protein (c-Ki-ras p21) and the two rho proteins (rho p20 and rho p21). smg p25A is present abundantly in brain and adrenal medulla. This G protein is also found in rat pheochromocytoma PC-12 cells, and its mRNA level increased after differentiation of the cells into neuron-like cells in response to nerve growth factor or dibutyryl cyclic AMP. These results suggest that smg p25A plays an important role in the regulation of neuronal functions. In contrast, smg p21 is found in most tissues. This G protein has the same putative effector domain as ras p21s, suggesting that smg p21 exerts the actions similar and/or antagonistic to those of ras p21s. In fact, smg p21 has been found to be identical with the protein encoded by the Krev-1 gene recently isolated as a gene suppressing the transforming action of Ki-ras p21 in NIH/3T3 cells. On the other hand, rho p20 and rho p21 are ADP-ribosylated by an ADP-ribosyltransferase contained or contaminated in botulinum toxin type C1, presumably C3. Botulinum ADP-ribosyltransferase C3 has recently been shown to induce morphological changes similar to those induced by ras p21 in fibroblasts. Thus, small Mr G proteins are part of a huge network of intracellular regulatory systems and play important roles in the regulation of various cell functions including cell transformation, proliferation and differentiation.
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PMID:Small molecular weight GTP-binding proteins and signal transduction. 251 26

The Ha-ras protooncogene product p21, which may be involved in control of cellular growth, is a membrane protein that binds guanine nucleotides and hydrolyzes GTP. p21 GTPase activity is stimulated by lysophosphatidylcholine; a delay in activation was observed unless p21 was incubated with the phospholipid prior to assay. Maximal activation by the phospholipid was observed over a narrow concentration range; the presence in the assay mixture of lysophosphatidylcholine at concentrations above this optimum markedly inhibited p21 GTPase. GTP hydrolysis was also stimulated, but to a lesser degree, by phosphatidylcholine. Phosphatidylinositol and phosphatidylserine did not significantly enhance GTPase activity. The stimulatory effect of phospholipid was mimicked, in part, by nonionic detergents. p21 may be related to other GTPases, the regulatory guanine nucleotide-binding G proteins of the hormone-sensitive adenylate cyclase complex and transducin of the retinal light-activated phosphodiesterase system. The G proteins and transducin are heterotrimers; the alpha subunits possess GTPase activity and the beta gamma subunit complex along with agonist-receptor complex or light-activated rhodopsin enhance GTP hydrolysis. p21 GTPase activity was slightly stimulated by rhodopsin, but, in contrast to the GTPase activity of transducin, stimulation was not light-dependent. GTP hydrolysis was enhanced somewhat by beta gamma subunit complex in the absence, but not in the presence, of rhodopsin. Like the G proteins and transducin, activity of p21 was altered by ADP-ribosylation. Modification of p21 catalyzed by an NAD: arginine ADP-ribosyltransferase purified from turkey erythrocytes decreased both GTPase activity and guanine nucleotide binding activity.
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PMID:Effects of phospholipids and ADP-ribosylation on GTP hydrolysis by Escherichia coli-synthesized Ha-ras-encoded p21. 300 95

A nuclear poly(ADP-ribose) polymerase (PARP) is activated by gamma-irradiation and consequently synthesizes poly(ADP-ribose) by binding to DNA strand-breaks. This property suggests that PARP is a DNA strand-break-signal generator. Meanwhile, the cell-cycle arrest occurs in G1 and G2 phases following gamma-irradiation. We found that PARP inhibitors including 3-aminobenzamide (3-AB) suppressed G1 arrest and enhanced G2 arrest following gamma-irradiation. These observations suggested that PARP is critical for the induction of G1 arrest and is also involved in the regulation of G2 arrest. Furthermore, the effects of 3-AB on the G1-arrest signal-transduction pathway were also studied. We found that p53 stabilization following gamma-irradiation was not inhibited but the p53-responsive transient increases of WAF1/CIP1/p21 and MDM-2 mRNA were suppressed by 3-AB. Therefore, it is suggested that PARP participates in G1-arrest signal-transduction pathway through the modulation of WAF1/CIP1/p21 and MDM-2 mRNA expression.
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PMID:Role of poly(ADP-ribose) polymerase in cell-cycle checkpoint mechanisms following gamma-irradiation. 757 30

An activator of rat brain phospholipase D (PLD) that is distinct from the already identified PLD activator, ADP-ribosylation factor (ARF), was partially purified from bovine brain cytosol by a series of chromatographic steps. The partially purified preparation contained a 22-kDa substrate for Clostridium botulinum C3 exoenzyme ADP-ribosyltransferase, which strongly reacted with anti-rhoA p21 antibody, but not with anti-rac1 p21 or anti-cdc42Hs p21 antibody. Treatment of the partially purified PLD-activating factor with both C3 exoenzyme and NAD significantly inhibited the PLD-stimulating activity. These results suggest that rhoA p21 is, at least in part, responsible for the PLD-stimulating activity in the preparation. Recombinant isoprenylated rhoA p21 expressed in and purified from Sf9 cells activated rat brain PLD in a concentration- and GTP gamma S (guanosine 5'-O-(3-thiotriphosphate))-dependent manner. In contrast, recombinant non-isoprenylated rhoA p21 (fused to glutathione S-transferase) expressed in Escherichia coli failed to activate the PLD. This difference cannot be explained by a lower affinity of non-isoprenylated rhoA p21 for GTP gamma S, as the rates of [35S]GTP gamma S binding were very similar for both recombinant preparations and the GTP gamma S-bound form of non-isoprenylated rhoA p21 did not induce PLD activation. Interestingly, recombinant isoprenylated rhoA p21 and ARF synergistically activated rat brain PLD; a similar pattern was seen with the partially purified PLD-activating factor. The synergistic activation was inhibited by C3 exoenzyme-catalyzed ADP-ribosylation of recombinant isoprenylated rhoA p21 in a NAD-dependent manner. Inhibition correlated with the extent of ADP-ribosylation. These findings suggest that rhoA p21 regulates rat brain PLD in concert with ARF, and that isoprenylation of rhoA p21 is essential for PLD regulation in vitro.
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PMID:Synergistic activation of rat brain phospholipase D by ADP-ribosylation factor and rhoA p21, and its inhibition by Clostridium botulinum C3 exoenzyme. 759 44

Clostridium botulinum C3 exoenzyme specifically ADP-ribosylates rho-p21 in eukaryotic cells. Trp18 and Glu173 of this enzyme were substituted with other amino acids via site-directed mutagenesis. All substitutions at Glu173 caused a significant reduction in affinity for NAD and diminished ADP-ribosyltransferase activity. On the other hand, the activity of enzymes with the substitution at Trp18 remained intact. Swiss 3T3 cells treated with the enzyme with the Trp18 substitution showed the typical morphologic changes of the C3 exoenzyme phenotype. In contrast, no changes were found in cells incubated with the Glu173-substituted enzyme. These results indicate that the Glu173 residue of the C3 exoenzyme plays a key role in interacting with NAD and in expression of ADP-ribosyltransferase activity, which is essential for the phenotypic change by C3 exoenzyme treatment.
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PMID:Identification of Glu173 as the critical amino acid residue for the ADP-ribosyltransferase activity of Clostridium botulinum C3 exoenzyme. 767 6

Rho protein (rho p21), a p21ras-related small guanine nucleotide binding protein, regulates cytoskeletal organization in a number of different types of cells. Evidence has indicated that Clostridium botulinum-derived ADP-ribosyltransferase (C3 exoenzyme) specifically ADP-ribosylates rho p21 at Asn41 and renders it functionally inactive. In this study, we examined the involvement of rho p21 in osteoclastic bone resorption using the C3 exoenzyme. When osteoclast-like multinucleated cells obtained from cocultures of mouse osteoblastic cells and bone marrow cells were placed on dentine slices, they formed ringed structures of podosomes containing F-actin (corresponding to the clear zone) within 8 hours. Many resorption pits were formed on dentine slices after culture for 24 hours. The C3 exoenzyme at 0.15-10 micrograms/ml added to the culture medium disrupted the ringed structure of podosomes in osteoclast-like cells in a dose-dependent manner. Correspondingly, pit formation by osteoclast-like cells on dentine slices was dose-dependently inhibited also by adding the C3 exoenzyme. Microinjection of the C3 exoenzyme into osteoclast-like cells placed on culture dishes completely disrupted the ringed podosome structure within 20 minutes. The amount of the rho p21 which was ADP-ribosylated by the C3 exoenzyme in vitro was much greater in purified osteoclast-like cells than in osteoblastic cells. Prior exposure of the purified osteoclast-like cell preparation to the C3 exoenzyme in vivo markedly decreased the amount of unribosylated rho p21. This indicated that the C3 exoenzyme incorporated into osteoclast-like cells effectively ADP-ribosylates rho p21 in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The small GTP-binding protein, rho p21, is involved in bone resorption by regulating cytoskeletal organization in osteoclasts. 767 48

rho GDP dissociation inhibitor (GDI) is an inhibitory GDP/GTP exchange protein for a group of small GTP-binding proteins including at least rhoA p21, rhoB p21, rac1 p21, rac2 p21, and G25K. Microinjection of rho GDI into Swiss 3T3 cells made the cells round and refractile. This morphological change was accompanied by the disappearance of stress fibers. The rho GDI action was prevented by comicroinjection of rho GDI with the guanosine 5'-(3-O-thio)triphosphate (GTP gamma S)-bound form of rhoA p21, but not with the GTP gamma S-bound form of rhoA p21 lacking the C-terminal three amino acids, which was not post-translationally modified with lipids. The GTP gamma S-bound form of rac1 p21, the same form of G25K, the same form of smg p21B, or Ki-rasval12 p21 was ineffective. Microinjection of the bacterial ADP-ribosyltransferase C3 specific for rho p21 into Swiss 3T3 cells induced the similar changes of morphology and stress fibers. This C3 action was not prevented by comicroinjection of C3 with the GTP gamma S-bound form of rhoA p21, but was prevented by comicroinjection with the same form of a rhoA p21 mutant which was not ADP-ribosylated by C3. These results indicate that the rho GDI-rho p21 system regulates cell morphology presumably through the actomyosin system in Swiss 3T3 cells.
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PMID:Regulation of morphology by rho p21 and its inhibitory GDP/GTP exchange protein (rho GDI) in Swiss 3T3 cells. 841 55


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