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)

AMPK acts as a cellular fuel gauge and responds to decreased cellular energy status by inhibiting ATP-consuming pathways and increasing ATP-synthesis. The aim of this study was to examine the role of AMPK in modulating poly(ADP-ribose) polymerase (PARP), a nuclear enzyme involved in maintaining chromatin structure and DNA repair. HT-29 cells infected with constitutively active AMPK demonstrated increased PARP automodification and an increase in bioNAD incorporation. AMPK and PARP co-immunoprecipitated under basal conditions and in response to H(2)O(2), suggesting a physical interaction under both resting and stress-induced conditions. Incubation of PARP with purified AMPK resulted in the phosphorylation of PARP; and the inclusion of AMP as an AMPK activator potentiated PARP phosphorylation. Using immobilized PARP, the incorporation of bioNAD by PARP was dramatically increased following the addition of AMPK. These data suggest a novel role for AMPK in regulating PARP activity through a direct interaction involving phosphorylation.
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PMID:AMP-activated protein kinase is a positive regulator of poly(ADP-ribose) polymerase. 1648 Sep 59

Following stimulation of NMDA receptors, neurons transiently synthesize nitric oxide (NO) in a calcium/calmodulin-dependent manner through the activation of neuronal NO synthase. Nitric oxide acts as a messenger, activating soluble guanylyl cyclase and participating in the transduction signalling pathways involving cyclic GMP. Nitric oxide also binds to cytochrome c oxidase, and is able to inhibit cell respiration in a process that is reversible and in competition with oxygen. This action can also lead to the release of superoxide anion from the mitochondrial respiratory chain. Here, we discuss recent evidence that this mitochondrial interaction represents a molecular switch for cell signalling pathways involved in the control of physiological functions. These include superoxide- or oxygen-dependent modulation of gene transcription, calcium-dependent cell signalling responses, changes in the mitochondrial membrane potential or AMP-activated protein kinase-dependent control of glycolysis. In pathophysiological conditions, such as brain ischaemia or neurological disorders, NO is formed excessively by NMDA receptor over-activation in neurons, or by inducible NO synthase from neighbouring glia (microglial cells and astrocytes). Elevated NO concentrations can then interact with superoxide anion, generated by the mitochondria or by other mechanisms, leading to the formation of the powerful oxidant species peroxynitrite. During pathological conditions activation of the NAD(+)-consuming enzyme poly(APD-ribose) polymerase-1 (PARP-1) is also a likely mechanism for NO-mediated energy failure and neurotoxicity. Activation of PARP-1 is, however, a repair process, which in milder forms of oxidative stress protects neurons from death. Thus, whilst NO plays a physiological role in neuronal cell signalling, its over-production may cause neuronal energy compromise leading to neurodegeneration.
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PMID:Nitric oxide, cell bioenergetics and neurodegeneration. 1680 76

Under oxidative stress, poly(ADP-ribose) polymerase-1 (PARP-1) is activated and contributes to necrotic cell death through ATP depletion. On the other hand, oxidative stress is known to stimulate autophagy, and autophagy may act as either a cell death or cell survival mechanism. This study aims to explore the regulatory role of PARP-1 in oxidative stress-mediated autophagy and necrotic cell death. Here, we first show that hydrogen peroxide (H(2)O(2)) induces necrotic cell death in Bax-/- Bak-/- mouse embryonic fibroblasts through a mechanism involving PARP-1 activation and ATP depletion. Next, we provide evidence that autophagy is activated in cells exposed to H(2)O(2). More importantly, we identify a novel autophagy signaling mechanism linking PARP-1 to the serine/threonine protein kinase LKB1-AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway, leading to stimulation of autophagy. Finally, we demonstrate that autophagy plays a cytoprotective role in H(2)O(2)-induced necrotic cell death, as suppression of autophagy by knockdown of autophagy-related gene ATG5 or ATG7 greatly sensitizes H(2)O(2)-induced cell death. Taken together, these findings demonstrate a novel function of PARP-1: promotion of autophagy through the LKB1-AMPK-mTOR pathway to enhance cell survival in cells under oxidative stress.
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PMID:A novel function of poly(ADP-ribose) polymerase-1 in modulation of autophagy and necrosis under oxidative stress. 2086 14

Poly(ADP-ribose) polymerase-1 (PARP-1), activated by DNA strand breaks, participates in the DNA repair process physiologically. Excessive activation of PARP-1 mediates necrotic cell death under the status of oxidative stress and DNA damage. However, it remains elusive whether and how PARP-1 activation is involved in autophagy and what is the function of PARP-1-mediated autophagy under oxidative stress and DNA damage. We recently demonstrated that hydrogen peroxide (H(2)O(2)) induces autophagy through a novel autophagy signaling mechanism linking PARP-1 activation to the LKB1-AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway. Furthermore, PARP-1-mediated autophagy plays a cytoprotective role in H(2)O(2)-induced necrotic cell death as suppression of autophagy greatly sensitizes H2O2- induced cell death. Our study thus identifies a novel function of PARP-1 in mediating autophagy and it appears that PAPR-1 possesses a dual role in modulating necrosis and autophagy under oxidative stress and DNA damage: on the one hand, overactivation of PARP-1 leads to ATP depletion and necrotic cell death; on the other hand, PARP-1 activation promotes autophagy via the LKB1- AMPK-mTOR pathway to enhance cell survival. The cellular decision of life or death depends on the balance between autophagy and necrosis mediated by these two distinct pathways.
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PMID:To die or to live: the dual role of poly(ADP-ribose) polymerase-1 in autophagy and necrosis under oxidative stress and DNA damage. 2107 16

Dopamine at 100-500 microM has toxic effects on human SH-SY5Y neuroblastoma cells, manifested as apoptotic cell loss and strong autophagy. The molecular mechanisms and types of dopamine-induced cell death are not yet well known. Their identification is important in the study of neurodegenerative diseases that specifically involve dopaminergic neurons. We looked for changes in expression and content of proteins involved in apoptosis and autophagy after dopamine treatment. All the changes found were prevented by avoiding dopamine oxidation with N-acetylcysteine, indicating a key role for the products of dopamine oxidation in dopamine toxicity. As early as 1-2h after treatment we found an increase in hypoxia-inducible factor-1alpha (HIF-1alpha) and an accumulation of ubiquitinated proteins. Proteins regulated by HIF-1alpha and involved in apoptosis and/or autophagy, such as p53, Puma and Bnip3, were subsequently increased. However, apoptotic parameters (caspase-3, caspase-7, PARP) were only activated after 12h of 500muM dopamine treatment. Autophagy, monitored by the LC3-II increase after LC3-I linkage to autophagic vacuoles, was evident after 6h of treatment with both 100 and 500 microM dopamine. The mTOR pathway was inhibited by dopamine, probably due to the intracellular redox changes and energy depletion leading to AMPK activation. However, this mechanism is not sufficient to explain the high LC3-II activation caused by dopamine: the LC3-II increase was not reversed by IGF-1, which prevented this effect when caused by the mTOR inhibitor rapamycin. Our results suggest that the aggregation of ubiquitinated non-degraded proteins may be the main cause of LC3-II activation and autophagy. As we have reported previously, cytosolic dopamine may cause damage by autophagy in neuroblastoma cells (and presumably in dopaminergic neurons), which develops to apoptosis and leads to cell degeneration.
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PMID:Effects of dopamine on LC3-II activation as a marker of autophagy in a neuroblastoma cell model. 1941 Jun 1

Triple negative (TN) breast cancer is more frequent in women who are obese or have type II diabetes, as well as young women of color. These cancers do not express receptors for the steroid hormones estrogen or progesterone, or the type II receptor tyrosine kinase (RTK) Her-2 but do have upregulation of basal cytokeratins and the epidermal growth factor receptor (EGFR). These data suggest that aberrations of glucose and fatty acid metabolism, signaling through EGFR and genetic factors may promote the development of TN cancers. The anti-type II diabetes drug metformin has been associated with a decreased incidence of breast cancer, although the specific molecular subtypes that may be reduced by metformin have not been reported. Our data indicates that metformin has unique anti-TN breast cancer effects both in vitro and in vivo. It inhibits cell proliferation (with partial S phase arrest), colony formation and induces apoptosis via activation of the intrinsic and extrinsic signaling pathways only in TN breast cancer cell lines. At the molecular level, metformin increases P-AMPK, reduces P-EGFR, EGFR, P-MAPK, P-Src, cyclin D1 and cyclin E (but not cyclin A or B, p27 or p21), and induces PARP cleavage in a dose- and time-dependent manner. These data are in stark contrast to our previously published biological and molecular effects of metformin on luminal A and B, or Her-2 type breast cancer cells. Nude mice bearing tumor xenografts of the TN line MDA-MB-231, treated with metformin, show significant reductions in tumor growth (p = 0.0066) and cell proliferation (p = 0.0021) as compared to untreated controls. Metformin pre-treatment, before injection of MDA-MB-231 cells, results in a significant decrease in tumor outgrowth and incidence. Given the unique anti-cancer activity of metformin against TN disease, both in vitro and in vivo, it should be explored as a therapeutic agent against this aggressive form of breast cancer.
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PMID:Metformin induces unique biological and molecular responses in triple negative breast cancer cells. 1971 81

Although compound K (CK), an intestinal metabolite of ginseng protopanaxadiol saponins, has been known to induce apoptosis in various cancer cells, association of AMP-activated protein kinase (AMPK) with apoptosis in HT-29 colon cancer cells remains unclear. We hypothesized that CK may exert an anticancer activity through modulating the AMPK pathway in HT-29 cells. CK-induced apoptosis was associated with the disruption of the mitochondrial membrane potential, release of apoptogenic factors (cytochrome c and apoptosis-inducing factor) from mitochondria, and cleavage of caspase-9, caspase-3, caspase-8, Bid, and PARP proteins. This apoptotic effect of CK on colon cancer cells was found to be initiated by AMPK activation, and AMPK was activated through phosphorylation by Ca2+/calmodulin-activated protein kinase-IV (CAMK-IV). Treatment of HT-29 cells with compound C (AMPK inhibitor) or siRNA for AMPK completely abolished the CK-induced apoptosis. STO-609, CAMKs inhibitor, also attenuated CK-induced AMPK activation and apoptosis. In conclusion, the present study demonstrates that CK-mediated cell death of HT-29 colon cancer cells is regulated by CAMK-IV/AMPK pathways, and these findings provide a molecular basis for the anticancer effect of CK.
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PMID:Compound K induces apoptosis via CAMK-IV/AMPK pathways in HT-29 colon cancer cells. 1984 53

There are multiple lines of evidence that persimmon extract and its constituents have potent antitumor activity against human cancer cells. However, the molecular mechanisms of 24-hydroxyursolic acid, a triterpenoid found in persimmon, on antitumor activities are not yet understood. Here, we demonstrate that 24-hydroxyursolic acid inhibited cell proliferation, strongly activated AMP-activated protein kinase (AMPK) and mediated critical anticancer effects by inhibition of cyclooxygenase (COX-2) expression in HT-29 cells. In addition, 24-hydroxyursolic acid induced cellular apoptosis by activation of poly(ADP-ribose) polymerase (PARP), caspase-3, and phosphorylation of p53 at Ser15. It also strongly induced DNA fragmentation in HT-29 cells and thereby significantly inhibited colony formation of HT-29 cells in soft agar. In addition, 24-hydroxyursolic acid blocked the EGF-induced ERKs phosphorylation and led to the inhibition of AP-1 activity and cell transformation in JB6 CL41 cells. Collectively, these findings are the first to reveal a molecular basis for the anticarcinogenic action of 24-hydroxyursolic acid and might account for the reported chemopreventive and chemotherapic effects of persimmon extracts.
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PMID:24-hydroxyursolic acid from the leaves of the Diospyros kaki (Persimmon) induces apoptosis by activation of AMP-activated protein kinase. 1996 Apr 11

The molecular mechanisms responsible for the association of obesity with adverse colon cancer outcomes are poorly understood. We investigated the effects of a high-energy diet on growth of an in vivo colon cancer model. Seventeen days following the injection of 5x10(5) MC38 colon carcinoma cells, tumors from mice on the high-energy diet were approximately twice the volume of those of mice on the control diet. These findings were correlated with the observation that the high-energy diet led to elevated insulin levels, phosphorylated AKT, and increased expression of fatty acid synthase (FASN) by the tumor cells. Metformin, an antidiabetic drug, leads to the activation of AMPK and is currently under investigation for its antineoplastic activity. We observed that metformin blocked the effect of the high-energy diet on tumor growth, reduced insulin levels, and attenuated the effect of diet on phosphorylation of AKT and expression of FASN. Furthermore, the administration of metformin led to the activation of AMPK, the inhibitory phosphorylation of acetyl-CoA carboxylase, the upregulation of BNIP3 and increased apoptosis as estimated by poly (ADP-ribose) polymerase (PARP) cleavage. Prior work showed that activating mutations of PI3K are associated with increased AKT activation and adverse outcome in colon cancer; our results demonstrate that the aggressive tumor behavior associated with a high-energy diet has similar effects on this signaling pathway. Furthermore, metformin is demonstrated to reverse the effects of the high-energy diet, thus suggesting a potential role for this agent in the management of a metabolically defined subset of colon cancers.
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PMID:Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. 2022 37

Damaged DNA can lead to aneuploidy and/or chromosomal instability, which is believed to be major contributor to tumor progression. DNA damage in response to genotoxic and oncogenic stresses activate the tumor suppressor pathways initiating DNA damage response (DDR). One of the cellular fates in response to DDR is permanent growth arrest in mitotically active cells, including stem cells, leading to senescence. On the other hand, DDR reasons in adaptive changes in postmitotic cells. These cellular alterations happen through complex interactions and function to disrupt the existing cellular homeostasis. Significant metabolic changes occurred by the influence of the major tumor suppressor protein p53 and other related factors such as FOXO, AMPK, PARP, NF-kappaB and PGC-1 are discussed in the article. After a strong correlation established between the systemic DNA damage response to inhibit ongoing malignant transformation and metabolic syndrome characteristics, logical extrapolations for type 2 diabetes, cardiovascular disease, and aging are carried out. Finally, therapeutic evaluations are performed in the light of the novel pathophysiological data implying that "metabolic syndrome" is a real disease.
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PMID:Systemic DNA damage response and metabolic syndrome as a premalignant state. 2033 25


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