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)

Sirtuins are homologues of the yeast transcriptional repressor Sir2p and are conserved from bacteria to humans. We report that human SIRT4 is localized to the mitochondria. SIRT4 is a matrix protein and becomes cleaved at amino acid 28 after import into mitochondria. Mass spectrometry analysis of proteins that coimmunoprecipitate with SIRT4 identified insulindegrading enzyme and the ADP/ATP carrier proteins, ANT2 and ANT3. SIRT4 exhibits no histone deacetylase activity but functions as an efficient ADP-ribosyltransferase on histones and bovine serum albumin. SIRT4 is expressed in islets of Langerhans and colocalizes with insulin-expressing beta cells. Depletion of SIRT4 from insulin-producing INS-1E cells results in increased insulin secretion in response to glucose. These observations define a new role for mitochondrial SIRT4 in the regulation of insulin secretion.
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PMID:Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. 1771 27

Sirtuins are a highly conserved family of proteins implicated in diverse cellular processes such as gene silencing, aging, and metabolic regulation. Although many sirtuins catalyze a well characterized protein/histone deacetylation reaction, there are a number of reports that suggest protein ADP-ribosyltransferase activity. Here we explored the mechanisms of ADP-ribosylation using the Trypanosoma brucei Sir2 homologue TbSIR2rp1 as a model for sirtuins that reportedly display both activities. Steady-state kinetic analysis revealed a highly active histone deacetylase (k cat = 0.1 s(-1), with Km values of 42 microm and for NAD+ and 65 microm for acetylated substrate). A series of biochemical assays revealed that TbSIR2rp1 ADP-ribosylation of protein/histone requires an acetylated substrate. The data are consistent with two distinct ADP-ribosylation pathways that involve an acetylated substrate, NAD+ and TbSIR2rp1 as follows: 1) a noncatalytic reaction between the deacetylation product O-acetyl-ADP-ribose (or its hydrolysis product ADP-ribose) and histones, and 2) a more efficient mechanism involving interception of an ADP-ribose-acetylpeptide-enzyme intermediate by a side-chain nucleophile from bound histone. However, the sum of both ADP-ribosylation reactions was approximately 5 orders of magnitude slower than histone deacetylation under identical conditions. The biological implications of these results are discussed.
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PMID:Acetylation-dependent ADP-ribosylation by Trypanosoma brucei Sir2. 1816 39

Micro-RNAs are approximately 21-25-nucleotide-long noncoding RNAs that regulate gene expression primarily at the post-transcriptional level in animals. Here, we report that micro-RNA-1 (miR-1), abundant in the cardiac and smooth muscles, is expressed in the lung and is down-regulated in human primary lung cancer tissues and cell lines. In situ hybridization demonstrated localization of miR-1 in bronchial epithelial cells. The tumor suppressor C/EBPalpha, frequently suppressed in lung cancer, reactivated miR-1 expression in the lung cancer cells. Repressed miR-1 was also activated in lung cancer cells upon treatment with a histone deacetylase inhibitor. These observations led us to examine the antitumorigenic potential of miR-1 in lung cancer cells. Expression of miR-1 in nonexpressing A549 and H1299 cells reversed their tumorigenic properties, such as growth, replication potential, motility/migration, clonogenic survival, and tumor formation in nude mice. Exogenous miR-1 significantly reduced expression of oncogenic targets, such as MET, a receptor tyrosine kinase, and Pim-1, a Ser/Thr kinase, frequently up-regulated in lung cancer. Similarly, the levels of two additional targets, FoxP1, a transcription factor with oncogeneic property, and HDAC4 that represses differentiation-promoting genes, were reduced in miR-1-expressing cells. Conversely, depletion of miR-1 facilitated N417 cell growth with concomitant elevation of these targets. Further, ectopic miR-1 induced apoptosis in A549 cells in response to the potent anticancer drug doxorubicin. Enhanced activation of caspases 3 and 7, cleavage of their substrate PARP-1, and depletion of anti-apoptotic Mcl-1 contributed to the sensitivity of miR-1-expressing cells to doxorubicin. Thus, miR-1 has potential therapeutic application against lung cancers.
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PMID:Down-regulation of micro-RNA-1 (miR-1) in lung cancer. Suppression of tumorigenic property of lung cancer cells and their sensitization to doxorubicin-induced apoptosis by miR-1. 3012 Jan 49

Neurons are excitable cells that require large amounts of energy to support their survival and functions and are therefore prone to excitotoxicity, which involves energy depletion. By examining bioenergetic changes induced by glutamate, we found that the cellular nicotinamide adenine dinucleotide (NAD(+)) level is a critical determinant of neuronal survival. The bioenergetic effects of mitochondrial uncoupling and caloric restriction were also examined in cultured neurons and rodent brain. 2, 4-dinitrophenol (DNP) is a chemical mitochondrial uncoupler that stimulates glucose uptake and oxygen consumption on cultured neurons, which accelerates oxidation of NAD(P)H to NAD(+) in mitochondria. The NAD(+)-dependent histone deacetylase sirtulin 1 (SIRT1) and glucose transporter 1 (GLUT1) mRNA are upregulated mouse brain under caloric restriction. To examine whether NAD(+) mediates neuroprotective effects, nicotinamide, a precursor of NAD(+) and inhibitor of SIRT1 and poly (ADP-ribose) polymerase 1 (PARP1) (two NAD(+)-dependent enzymes), was employed. Nicotinamide attenuated excitotoxic death and preserved cellular NAD(+) levels to support SIRT1 and PARP 1 activities. Our findings suggest that mild mitochondrial uncoupling and caloric restriction exert hormetic effects by stimulating bioenergetics in neurons thereby increasing tolerance of neurons to metabolic stress.
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PMID:Preventing NAD(+) depletion protects neurons against excitotoxicity: bioenergetic effects of mild mitochondrial uncoupling and caloric restriction. 1907 49

To examine the function of SIRT1 in neuronal differentiation, we employed all-trans retinoic acid (ATRA)-induced differentiation of neuroblastoma cells. Nicotinamide inhibited neurite outgrowth and tyrosine hydroxylase (TH) expression. Inhibition of PARP or histone deacetylase did not inhibit TH expression, showing the effect to be SIRT1 specific. Expression of FOXO3a and its target proteins were increased during the differentiation and reduced by nicotinamide. FOXO3a deacetylation was increased by ATRA and blocked by nicotinamide. SIRT1 and FOXO3a siRNA inhibited ATRA-induced up-regulation of TH and differentiation. Taken together, these results indicate that SIRT1 is involved in ATRA-induced differentiation of neuroblastoma cells via FOXO3a.
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PMID:SIRT1 regulates tyrosine hydroxylase expression and differentiation of neuroblastoma cells via FOXO3a. 1928 77

Pituitary adenomas, which account for 15-20% of intracranial tumors, are associated with significant morbidity and mortality, due in part, to hormone hypersecretion and mass effects following increased proliferation. Radiotherapy and surgery remain frontline treatment options; however, adverse side effects and surgical limitations to treat invasive tumors necessitate the need for novel therapeutic targets. This study tested the efficacy of the histone deacetylase inhibitor (HDACi), suberoylanilide hydroxamic acid (SAHA) in GH3, and MMQ pituitary adenoma cells. Clinically achievable concentrations of SAHA (500 nM-4 microM) induced growth arrest and increased cell death in GH3 pituitary adenoma cells. Further investigation into the mechanism of cell death revealed an increase in PARP cleavage and procaspase-3 activation, consistent with apoptotic cell death. SAHA also attenuated the expression of anti-apoptotic IAP (XIAP, survivin) and Bcl-2 family proteins (Bcl-2, Bcl-xL), but did not alter Bax expression. Together, these findings support a possible utility for SAHA alone or in combination with radiation for the treatment of pituitary adenoma.
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PMID:Suberoylanilide hydroxamic acid (SAHA) induces growth arrest and apoptosis in pituitary adenoma cells. 1929 26

We evaluated the novel gamma-lactam-based analogue, KBH-A145, for its anticancer activities. KBH-A145 markedly inhibited histone deacetylase (HDAC) activity in vitro and in vivo to an extent comparable to suberoyl-anilide hydroxamic acid (SAHA). The proliferation of various types of cancers was significantly suppressed by KBH-A145, among which MDA-MB-231 and MCF, human breast cancer cells and ACHN human renal cancer cells, were most sensitive. This was accompanied by induction of p21(WAF1/Cip1) through compromised recruitment of HDAC1, which leads to hyperacetylation of its promoter region and thus arrested both cells in the G(2)/M phase. Interestingly, this compound induced apoptosis of MDA-MB-231 cells, but not ACHN cells, through cleavage of poly(ADP-ribose) polymerase (PARP). Taken together, these results show that this novel gamma-lactam-based HDAC inhibitor potently inhibits the growth of human breast and renal cancer cells. Thus KBH-A145 is a potential therapeutic agent for the treatment of these types of cancer.
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PMID:A novel gamma-lactam-based histone deacetylase inhibitor potently inhibits the growth of human breast and renal cancer cells. 1980 34

The objective of this study was to evaluate molecular markers involved in mammary tumorigenesis in a canine model that mimics many essential elements of human breast cancer. Thirty mammary gland tumors and control tissues obtained from female dogs were included in the study. We analyzed changes in the expression of markers of hormone and receptor status (estradiol, estrogen receptor; ER and HER-2/neu), hormone metabolism (CYP1A1 and CYP1B1), cell proliferation and survival [proliferating cell nuclear antigen (PCNA), glutathione S-transferase-P (GST-P), nuclear factor-kappaB (NF-kappaB-p50, NF-kappaB-p65), phosphorylated-inhibitor of kappaB-alpha (p-IkappaB-alpha) and IkappaB], apoptosis (Bcl-2, Bax, caspases, Apaf-1, cytochrome-C, and PARP), invasion [matrix metalloproteinases-2 and -9 (MMP-2, MMP-9), tissue inhibitor of matrix metalloproteinase-2 (TIMP-2), and reversion-inducing cysteine-rich protein with Kazal motifs (RECK)], angiogenesis [vascular endothelial growth factor (VEGF)], and epigenetics [DNA methyltransferase (Dnmt-1), histone deacetylase (HDAC-1)] by immunohistochemical localization and Western blot analysis and correlated these with histological grade. The present study provides evidence that increased expression of ER, HER-2/neu, estradiol, and its metabolizing enzymes, as well as proteins involved in cell proliferation, apoptosis evasion, invasion, and angiogenesis may confer a selective growth advantage to canine mammary tumors. To our knowledge this is the first report on the hallmark capabilities of canine mammary tumors, which lends credence to the view that the dog is a valuable model for human breast cancer studies.
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PMID:Evaluation of molecular markers in canine mammary tumors: correlation with histological grading. 2022 57

Benzene is an established hematotoxic carcinogen which can cause leukemia. DNA damage and disorder of repair capacity are the crucial mechanisms in leukemogenesis of benzene. DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (5-aza) and histone deacetylase inhibitor, trichostatin A (TSA) are two kinds of key epigenetic modification reagents. The mRNA expression of poly(ADP-ribose) polymerases-1 (PARP-1), a pivotal repair gene, has been decreased by benzene. However, the effect of epigenetic modification on benzene-induced low PARP-1 expression has not been reported. In this study, lymphoblastoid cell line F32 was incubated by benzene and then further treated with 5-aza and TSA, alone or in combination. The reverse transcription-polymerase chain reaction and methylation-specific PCR were performed to examine the mRNA expression and methylation status of PARP-1, respectively. Results showed a dramatic decrease of PARP-1 mRNA expression and a simultaneously obvious increase in the level of PARP-1 methylation in benzene-treated cells compared to the control. Further, the PARP-1 mRNA expression was restored and the level of PARP-1 methylation was also reduced following epigenetic inhibitors, 5-aza and TSA, alone or in combination treatments. Taken together, methylation of PARP-1 promoter might be involved in the regulation of benzene-induced decrease of PARP-1 mRNA expression.
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PMID:Methylation of PARP-1 promoter involved in the regulation of benzene-induced decrease of PARP-1 mRNA expression. 2023 Aug 82

As histone deacetylase inhibitors such as romidepsin (depsipeptide, FK228) complete successful Phase I clinical trials in pediatric solid tumors, it is important that their mechanisms of action are delineated in order to inform the development of subsequent clinical trials as single agents or in combination therapies. In this study, we evaluate the effect of romidepsin as a single agent on a number of different neuroblastoma (NB) cell lines. We find that the growth of 6/6 human NB tumor cell lines but not an immortalized fibroblast cell line (NIH3T3) is inhibited by romidepsin (IC(50) = 1-6.5 ng/ml) after 72 h of treatment. Romidepsin shows selective dose-dependent cytotoxicity in both single copy and N-myc amplified NB cell lines, in cell lines with wild type or mutant p53 and those containing Alk mutations. The decrease in cell proliferation is accompanied by caspase-dependent apoptosis as shown by PARP cleavage, an accumulation of cells in the sub-G(1) phase of the cell cycle and the ability of a pan-caspase inhibitor to reduce cell death. Romidepsin inhibits the growth of subcutaneous NB xenografts in a dose dependent manner in immunocompromised mice. Furthermore, romidepsin induces expression of genes such as p21 and expression of p75 and NTRK (TrkA) which are more highly expressed in the tumors from NB patients that have a good prognosis. These studies support continued investigations into the therapeutic activity of romidepsin in NB.
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PMID:Romidepsin (FK228/depsipeptide) controls growth and induces apoptosis in neuroblastoma tumor cells. 2040 60


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