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)

Incubation of cultured rat hepatocytes with sodium nitroprusside or SIN-1, two nitric oxide (NO) donors, inhibited the mitogenic action of hepatocyte growth factor in a dose-dependent manner. The addition of 100 microM reduced hemoglobin, which is known to absorb NO, or the presence of 20 microM 1,5-isoquinolinediol, a poly(ADP-ribose) polymerase (PARP) inhibitor, decreased the cytostatic effects of SIN-1. By labeling the hepatocytes with [2-3H]adenine we studied whether nitric oxide induces ADP-ribosylation of proteins in a whole-cell system. At 0.4 mM, sodium nitroprusside increased the [3H]adenine labeling of two proteins of 116 and 130-135 kDa. This effect was time-dependent and was detected after 2 h. Only the 116-kDa protein was recognized by three different antibodies against poly (ADP-ribose) polymerase in Western blot assays. These results demonstrate that NO has antimitogenic effects in cultured hepatocytes and that its action could be mediated by PARP activation.
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PMID:Nitric oxide inhibits DNA synthesis and induces activation of poly(ADP-ribose) polymerase in cultured rat hepatocytes. 889 65

Rho-associated kinase (Rho-kinase), which is activated by the small GTPase Rho, phosphorylates myosin-binding subunit (MBS) of myosin phosphatase and thereby inactivates the phosphatase activity in vitro. Rho-kinase is thought to regulate the phosphorylation state of the substrates including myosin light chain (MLC), ERM (ezrin/radixin/moesin) family proteins and adducin by their direct phosphorylation and by the inactivation of myosin phosphatase. Here we identified the sites of phosphorylation of MBS by Rho-kinase as Thr-697, Ser-854 and several residues, and prepared antibody that specifically recognized MBS phosphorylated at Ser-854. We found by use of this antibody that the stimulation of MDCK epithelial cells with tetradecanoylphorbol-13-acetate (TPA) or hepatocyte growth factor (HGF) induced the phosphorylation of MBS at Ser-854 under the conditions in which membrane ruffling and cell migration were induced. Pretreatment of the cells with Botulinum C3 ADP-ribosyltransferase (C3), which is thought to interfere with Rho functions, or Rho-kinase inhibitors inhibited the TPA- or HGF-induced MBS phosphorylation. The TPA stimulation enhanced the immunoreactivity of phosphorylated MBS in the cytoplasm and membrane ruffling area of MDCK cells. In migrating MDCK cells, phosphorylated MBS as well as phosphorylated MLC at Ser-19 were localized in the leading edge and posterior region. Phosphorylated MBS was localized on actin stress fibers in REF52 fibroblasts. The microinjection of C3 or dominant negative Rho-kinase disrupted stress fibers and weakened the accumulation of phosphorylated MBS in REF52 cells. During cytokinesis, phosphorylated MBS, MLC and ERM family proteins accumulated at the cleavage furrow, and the phosphorylation level of MBS at Ser-854 was increased. Taken together, these results indicate that MBS is phosphorylated by Rho-kinase downstream of Rho in vivo, and suggest that myosin phosphatase and Rho-kinase spatiotemporally regulate the phosphorylation state of Rho-kinase substrates including MLC and ERM family proteins in vivo in a cooperative manner.
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PMID:Phosphorylation of myosin-binding subunit (MBS) of myosin phosphatase by Rho-kinase in vivo. 1057 22

Hepatocyte growth factor/scatter factor (HGF/SF) induces cell scattering through the tyrosine kinase-type HGF/SF receptor c-Met. We have previously shown that Rho small G protein (Rho) is involved in the HGF/SF-induced scattering of Madin-Darby canine kidney (MDCK) cells by regulating at least the assembly and disassembly of stress fibers and focal adhesions, but it remains unknown how c-Met regulates Rho activity. We have found here a novel signaling pathway of c-Met consisting of SHP-2-Rho that regulates the assembly and disassembly of stress fibers and focal adhesions in MDCK cells. SHP-2 is a protein-tyrosine phosphatase that contains src homology-2 domains. Expression of a dominant negative mutant of SHP-2 (SHP-2-C/S) markedly increased the formation of stress fibers and focal adhesions in MDCK cells and inhibited their scattering. C3, a Clostridium botulinum ADP-ribosyltransferase, and Y-27632, a specific inhibitor for ROCK, reversed the stimulatory effect of SHP-2-C/S on stress fiber formation and the inhibitory effect on cell scattering. Vav2 is a GDP/GTP exchange protein for Rho. Expression of a dominant negative mutant of Vav2 blocked the stimulatory effect of SHP-2-C/S on stress fiber formation. Conversely, expression of mutants of Vav2 that increased stress fiber formation inhibited HGF/SF-induced cell scattering. These results indicate that SHP-2 physiologically modulates the activity of Rho to form stress fibers and focal adhesions and thereby regulates HGF/SF-induced cell scattering. In addition, Vav2 may be involved in the SHP-2-Rho pathway.
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PMID:Involvement of an SHP-2-Rho small G protein pathway in hepatocyte growth factor/scatter factor-induced cell scattering. 1093 Apr 54

Our recent studies have shown ExoS to be a bifunctional type-III secreted cytotoxin. Intracellular expression of the amino terminus of ExoS (C234) in eukaryotic cells stimulates actin reorganization without cytotoxicity, which involves small-molecular-weight GTPases of the Rho subfamily. Expression of the carboxyl terminus of ExoS comprises an ADP-ribosyltransferase domain, which is cytotoxic when expressed in cultured cells (Pederson and Barbieri, 1998). Rho and Ras are molecular switches, which control numerous cellular processes. Recent signaling studies suggest that there is crosstalk between Rho and Ras (Keely et al, 1997). Ras and Rho also contribute to wound healing processes and tissue regeneration. Recent studies have shown that microinjection of endothelial cells with activated Ras stimulated their motility, while microinjection of Ras-blocking antibodies inhibited cellular motility that is a component of the wound healing process (Fox et al., 1994). In addition, hepatocyte growth factor/scatter factor (HGF/ SF) and epidermal growth factor stimulate cellular motility through the Ras signal transduction pathway (Ridley et al., 1995). Rac and Rho are also involved in motility and tissue regeneration, since dominant negative Rac inhibits the cellular motility stimulated by HGF/SF (Santos et al., 1997) and inhibition of Rho by either C. difficile ToxA and ToxB or the C. botulinum C3 transferase inhibits wound healing (Santos et al., 1997). Inhibition of tissue regeneration and wound healing appear to play a role in the pathogenesis of C. difficile, since treatment of gastrointestinal mucosa with C. difficile ToxA and ToxB alone inhibits regeneration of the gastric mucosa. Thus, ExoS may contribute to the establishment of P. aeruginosa infections by inhibiting wound healing and tissue regeneration by two mechanisms. The amino terminus of ExoS could inhibit Rho function and wound healing in a manner similar to C. difficile. Alternatively, ExoS could inhibit the cellular motility and angiogenesis required for wound healing by ADP-ribosylating Ras. Through the inhibition of tissue regeneration and wound healing, ExoS may play a pivotal role in chronic disease by maintaining sites of colonization. Inhibition of Ras or Rho signaling may also interfere with both innate and acquired immunity. Small-molecular-weight GTP-binding proteins of the Ras superfamily are required for cellular processes, such as phagocytosis, as Rho proteins contribute to phagocytosis (Caron and Hall, 1998). Since Ras functions upstream of Rho in cellular signaling processes (Ridley et al., 1995), ADP-ribosylation of Ras by ExoS or the inhibition of Rho function by C234 may inhibit phagocytosis of P. aeruginosa by macrophages. Other studies indicate that Ras plays a role in T cell activation (Cantrell, 1994). Thus, ExoS may inhibit acquired immunity by inhibiting T-cell activation.
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PMID:Pseudomonas aeruginosa exoenzyme S, a bifunctional type-III secreted cytotoxin. 1111 15

The cytokine hepatocyte growth factor/scatter factor (HGF/SF) has been found to protect a variety of epithelial and cancer cell types against cytotoxicity and apoptosis induced by DNA damage, but the specific apoptotic signaling events and the levels at which they are blocked by HGF/SF have not been identified. We found that treatment of MDA-MB-453 human breast cancer cells with adriamycin (also known as doxorubicin, a DNA topoisomerase IIalpha inhibitor) induced a series of time-dependent events, including the mitochondrial release of cytochrome c and apoptosis-inducing factor, mitochondrial membrane depolarization, activation of a set of caspases (caspase-9, -3, -7, -2, and -8), cleavage of poly(ADP-ribose) polymerase (PARP), and up-regulation of expression of the Fas ligand. All of these events were blocked by preincubation of the cells with HGF/SF. In contrast, the pan-caspase inhibitor benzyloxycarbonyl-VAD-fluoromethylketone blocked some of these events (e.g. caspase-3 activation and PARP cleavage) but did not block cytochrome c release or mitochondrial depolarization. These findings suggest that HGF/SF functions, in part, upstream of the mitochondria to block mitochondrial apoptosis signaling, prevent activation of multiple caspases, and protect breast cancer cells against apoptosis.
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PMID:Hepatocyte growth factor/scatter factor blocks the mitochondrial pathway of apoptosis signaling in breast cancer cells. 1157 Dec 97

In the present study, the pathways involved in oxidant-induced cell death of a primary cell of the retina, ARPE-19, were investigated and compared with a leukemic cell, U937 cells. Both ARPE-19 and U937 cells exhibited similar viability when exposed to menadione. At lethal doses, both cell lines demonstrated extensive membrane blebbing. However, although U937 cells exhibited caspase-3, -9 PARP cleavage and 200 bp laddering, no such cleavage or laddering was noted in ARPE-19 cells. Furthermore, addition of exogenous cytochrome c and ATP to a cell-free system again resulted in cleavage of caspase-3 and -9 in extracts of U937 but not ARPE cells. Further studies in ARPE-19 cells undergoing menadione-induced cell death demonstrated mitochondrial membrane depolarization, release of cytochrome c, nuclear translocation of apoptosis-inducing factor and subsequent 50 kilo-base pair laddering, and nuclear shrinkage. All of these findings were abrogated by the pretreatment of ARPE-19 cells with hepatocyte growth factor/scatter factor. These findings demonstrate the complex nature of cell death in primary cells of the retina and highlight the role of caspase-independent signals, growth factors and intracellular survival factors in programmed cell death pathways.
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PMID:Oxidant-induced cell death in retinal pigment epithelium cells mediated through the release of apoptosis-inducing factor. 1266 24

Hepatocyte growth factor (HGF) is one of the prospective agents for therapy against a variety of neurologic and neurodegenerative disorders, although the precise mechanisms for the effect of HGF remain to be elucidated. We showed that treatment with HGF protected hippocampal cornu ammonis (CA) subregion 1 neurons from apoptotic cell death after transient forebrain ischemia. Accumulating evidence indicates that ischemia-induced neuronal damage occurs via caspase-independent pathways. In the present study, we focused on the localization of apoptosis-inducing factor (AIF), which is an important protein in the signal-transduction system through caspase-independent pathways, to investigate the possible mechanism for the protective effect of HGF after transient forebrain ischemia. Hepatocyte growth factor attenuated the increase in the expression of AIF protein in the nucleus after transient forebrain ischemia. We further explored the upstream components of AIF translocation. Primary DNA damage induced by Ca(2+) influx and subsequent NO formation are thought to be the initial events for AIF translocation, which results in the subsequent DNA damage by AIF. Hepatocyte growth factor prevented the primary oxidative DNA damage, as was estimated by using anti-8-OHdG (8-hydroxy-2'-deoxyguanosine) antibody. Oxidative DNA damage after ischemia is known to lead to the activation of poly(ADP-ribose) polymerase (PARP) and p53, resulting in AIF translocation. Marked increases in the PAR polymer formation and the expression of p53 protein after ischemia were effectively prevented by HGF treatment. In the present study, we first showed that HGF was capable of preventing neuronal cell death by inhibiting the primary oxidative DNA damage and then preventing the activation of the PARP/p53/AIF pathway.
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PMID:Prevention of apoptosis-inducing factor translocation is a possible mechanism for protective effects of hepatocyte growth factor against neuronal cell death in the hippocampus after transient forebrain ischemia. 1651 2

c-Met, a receptor tyrosine kinase and its ligand, hepatocyte growth factor, are critical in cellular proliferation, motility and invasion and confer resistance to specific chemotherapeutic drugs. However, little is known about the impact of c-Met knockdown on the biological functions of human multiple myeloma U266 cells. The present study was designed to determine the role of c-Met in the proliferation and invasion of U266 cells, using RNA interference technology in vitro. In our study, the c-Met short hairpin RNA (shRNA) was successfully transfected into U266 cells, which resulted in the significant inhibition of transcription and expression of c-Met. The down-regulation of c-Met inhibited the proliferation potential, adherence and invasiveness of U266 cells, and also increased chemosensitivity to doxorubicin. The c-Met shRNA in U266 cells induced apoptosis and increased the accumulation of cleavage PARP and cleavage caspase-3. However, the expression of Bcl-2 and Bax did not change following the c-Met knockdown. Taken together, our data reveal that the down-regulation of c-Met inhibits proliferation and invasion and increases the chemosensitivity of U266 cells. Thus, the targeting of c-Met could be an effective therapeutic approach against multiple myeloma.
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PMID:Knockdown of c-Met inhibits cell proliferation and invasion and increases chemosensitivity to doxorubicin in human multiple myeloma U266 cells in vitro. 2146 75

Among many cancer therapeutic targets, c-Met receptor tyrosine kinase has recently given particular attention. This kinase and its ligand, hepatocyte growth factor (HGF), play a central role in cell proliferation and the survival of several human cancers. Thus, we developed KRC-408 as a novel c-Met inhibitor and investigated its anti-cancer effects on human gastric cancer. KRC-408 inhibited the phosphorylation of c-Met and its constitutive downstream effectors such as phosphatidylinositol 3-kinase (PI3K), Akt, Mek, and Erk. This compound was found to exert anti-cancer effects stronger than those of 5-fluorouracil (5-FU) on gastric cancer cells, especially cell lines that overexpressed c-Met. Interestingly, cytotoxicity of KRC-408 was lower than that of 5-FU in normal gastric cells. Apoptosis induced by KRC-408 was accompanied by increased levels of cleaved caspase-3 and PARP as well as DNA condensation and fragmentation. Flow cytometry analysis showed an accumulation of gastric cancer cells in the G2/M phase with concomitant loss of cells in the S phase following treatment with this drug. In the angiogenesis studies, KRC-408 inhibited tube formation and migration of human umbilical vein endothelial cells (HUVECs), and suppressed microvessel sprouting from rat aortic rings ex vivo along with blood vessel formation in a Matrigel plug assay in mice. Results of an in vivo mouse xenograft experiment showed that the administration of KRC-408 significantly delayed tumor growth in a dose-dependent manner, and suppressed Akt and Erk phosphorylation as well CD34 expression in tumor tissues. These findings indicate that KCR-408 may exert anti-tumor effects by directly affecting tumor cell growth or survival via the c-Met receptor tyrosine kinase pathway. We therefore suggest that KRC-408 is a novel therapeutic candidate effective against gastric cancers that overexpress c-Met.
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PMID:KRC-408, a novel c-Met inhibitor, suppresses cell proliferation and angiogenesis of gastric cancer. 2334 94

The anaplastic lymphoma kinase (ALK) and the c-Met receptor tyrosine kinase play essential roles in the pathogenesis in multiple human cancers and present emerging targets for cancer treatment. Here, we describe CM-118, a novel lead compound displaying low nanomolar biochemical potency against both ALK and c-Met with selectivity over>90 human kinases. CM-118 potently abrogated hepatocyte growth factor (HGF)-induced c-Met phosphorylation and cell migration, phosphorylation of ALK, EML4-ALK, and ALK resistance mutants in transfected cells. CM-118 inhibited proliferation and/or induced apoptosis in multiple c-Met- and ALK-addicted cancer lines with dose response profile correlating target blockade. We show that the CM-118-induced apoptosis in c-Met-amplified H1993 NSCLC cells involved a rapid suppression of c-Met activity and c-Met-to-EGFR cross-talk, and was profoundly potentiated by EGFR inhibitors as shown by the increased levels of apoptotic proteins cleaved-PARP and Bim as well as reduction of the survival protein Mcl-1. Bim-knockdown or Mcl-1 overexpression each significantly attenuated apoptosis. We also revealed a key role by mTOR in mediating CM-118 action against the EML4-ALK-dependent NSCLC cells. Abrogation of EML4-ALK in H2228 cells profoundly reduced signaling capacity of the rapamycin-sensitive mTOR pathway leading to G 1 cell cycle arrest and mitochondrial hyperpolarization, a metabolic perturbation linked to mTOR inhibition. Depletion of mTOR or mTORC1 inhibited H2228 cell growth, and mTOR inhibitors potentiated CM-118's antitumor activity in vitro and in vivo. Oral administration of CM-118 at a wide range of well tolerated dosages diminished c-Met- and ALK phosphorylation in vivo, and caused tumor regression or growth inhibition in multiple c-Met- and ALK-dependent tumor xenografts in mice. CM-118 exhibits favorable pharmacokinetic and drug metabolism properties hence presents a candidate for clinical evaluation.
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PMID:A novel lead compound CM-118: antitumor activity and new insight into the molecular mechanism and combination therapy strategy in c-Met- and ALK-dependent cancers. 2461 93


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