Abstract:
:Excessive activation of poly(ADP-ribose) polymerase 1 (PARP1) leads to NAD(+) depletion and cell death during ischemia and other conditions that generate extensive DNA damage. When activated by DNA strand breaks, PARP1 uses NAD(+) as substrate to form ADP-ribose polymers on specific acceptor proteins. These polymers are in turn rapidly degraded by poly(ADP-ribose) glycohydrolase (PARG), a ubiquitously expressed exo- and endoglycohydrolase. In this study, we examined the role of PARG in the PARP1-mediated cell death pathway. Mouse neuron and astrocyte cultures were exposed to hydrogen peroxide, N-methyl-d-aspartate (NMDA), or the DNA alkylating agent, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Cell death in each condition was markedly reduced by the PARP1 inhibitor benzamide and equally reduced by the PARG inhibitors gallotannin and nobotanin B. The PARP1 inhibitor benzamide and the PARG inhibitor gallotannin both prevented the NAD(+) depletion that otherwise results from PARP1 activation by MNNG or H(2)O(2). However, these agents had opposite effects on protein poly(ADP-ribosyl)ation. Immunostaining for poly(ADP-ribose) on Western blots and neuron cultures showed benzamide to decrease and gallotannin to increase poly(ADP-ribose) accumulation during MNNG exposure. These results suggest that PARG inhibitors do not inhibit PARP1 directly, but instead prevent PARP1-mediated cell death by slowing the turnover of poly(ADP-ribose) and thus slowing NAD(+) consumption. PARG appears to be a necessary component of the PARP-mediated cell death pathway, and PARG inhibitors may have promise as neuroprotective agents.
journal_name
Proc Natl Acad Sci U S Aauthors
Ying W,Sevigny MB,Chen Y,Swanson RAdoi
10.1073/pnas.211202598keywords:
subject
Has Abstractpub_date
2001-10-09 00:00:00pages
12227-32issue
21eissn
0027-8424issn
1091-6490pii
98/21/12227journal_volume
98pub_type
杂志文章abstract::Avian leukosis virus subgroup J (ALV-J) is an important concern for the poultry industry. Replication of ALV-J depends on a functional cellular receptor, the chicken Na+/H+ exchanger type 1 (chNHE1). Tryptophan residue number 38 of chNHE1 (W38) in the extracellular portion of this molecule is a critical amino acid for...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1913827117
更新日期:2020-01-28 00:00:00
abstract::Preliminary x-ray diffraction data from single crystals of the MoFe proteins of nitrogenase from Clostridium pasteurianum and Azotobacter vinelandii have been obtained. Both protein crystals belong to the P2(1) space group. The MoFe protein crystals from C. pasteurianum and A. vinelandii diffract to angles correspondi...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.79.2.378
更新日期:1982-01-01 00:00:00
abstract::The type II cell of the alveolar epithelium of adult rats has been studied by electron microscopy to determine its ability to endocytose electron-dense tracers of differing molecular charge and size. The tracers studied were native (anionic) ferritin, cationic ferritin, 70-kilodalton dextran, and colloidal carbon. Alv...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.81.19.6054
更新日期:1984-10-01 00:00:00
abstract::We use age distributions of sea otters (Enhydra lutris) found dead on beaches of western Prince William Sound, Alaska, between 1976 and 1998 in conjunction with time-varying demographic models to test for lingering effects from the 1989 Exxon Valdez oil spill. Our results show that sea otters in this area had decrease...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.120163397
更新日期:2000-06-06 00:00:00
abstract::The multiwavelength anomalous diffraction (MAD) method for phase evaluation is now widely used in macromolecular crystallography. Successful MAD structure determinations have been carried out at the K or L absorption edges of a variety of elements. In this study, we investigate the anomalous scattering properties of u...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.191003998
更新日期:2001-09-11 00:00:00
abstract::The population genetic consequences of nearest-neighbor pollination in an outcrossing plant species were investigated through computer simulations. The genetic system consisted of two alleles at a single locus in a self-incompatible plant that mates by random pollen transfer from a neighboring individual. Beginning wi...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.79.1.203
更新日期:1982-01-01 00:00:00
abstract::We have investigated the differentiation potential of precursor cells within the developing spinal cord of mice and have shown that spinal cord cells from embryonic day 10 specifically give rise to neurons when plated onto an astrocytic monolayer, Ast-1. These neurons had the morphology of motor neurons and > 83% expr...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.92.22.10079
更新日期:1995-10-24 00:00:00
abstract::Intact DNA molecules extracted from HSV-1 (herpes simplex virus 1, human herpes virus 1) strain MP virions have a molecular weight of approximately 97 X 10(6), but cleavage with the HinIII restriction enzyme yields fourteen fragments with summed molecular weights of 160 X 10(6). Six "major" fragments occur once in eve...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.72.11.4243
更新日期:1975-11-01 00:00:00
abstract::The vacuolated lens (vl) mouse mutant causes congenital cataracts and neural tube defects (NTDs), with the NTDs being caused by abnormal neural fold apposition and fusion. Our positional cloning of vl indicates these phenotypes result from a deletion mutation in an uncharacterized orphan G protein-coupled receptor (GP...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0705657105
更新日期:2008-02-12 00:00:00
abstract::Volcanic eruptions caused major weather and climatic changes on timescales ranging from hours to centuries in the past. Volcanic particles are injected in the atmosphere both as primary particles rapidly deposited due to their large sizes on time scales of minutes to a few weeks in the troposphere, and secondary parti...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1104923108
更新日期:2011-07-26 00:00:00
abstract::The amounts of mRNAs encoding alpha 1, alpha 6, beta 2, beta 3, gamma 2, and delta subunits of gamma-aminobutyrate type A (GABAA) receptors and the gold immunolabeling density of their translation products were monitored during the growth of neonatal rat granule cells in primary culture. We investigated possible corre...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.91.23.10952
更新日期:1994-11-08 00:00:00
abstract::The antitumor drug Taxol stabilizes microtubules and reduces their dynamicity, promoting mitotic arrest and cell death. Upon assembly of the alpha/beta-tubulin heterodimer, GTP bound to beta-tubulin is hydrolyzed to GDP reaching a steady-state equilibrium between free tubulin dimers and microtubules. The binding of Ta...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0603704103
更新日期:2006-07-05 00:00:00
abstract::All decisions, whether they are personal, public, or business-related, are based on the decision maker's beliefs and values. Science can and should help decision makers by shaping their beliefs. Unfortunately, science is not easily accessible to decision makers, and scientists often do not understand decision makers' ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1213532110
更新日期:2013-08-20 00:00:00
abstract::Surface functionalization of semiconductors has been the backbone of the newest developments in microelectronics, energy conversion, sensing device design, and many other fields of science and technology. Over a decade ago, the notion of viewing the surface itself as a chemical reagent in surface reactions was introdu...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1006656107
更新日期:2011-01-18 00:00:00
abstract::We quantitatively analyzed, using laser scanning confocal microscopy, the three-dimensional structure of individual senile plaques in Alzheimer disease. We carried out the quantitative analysis using statistical methods to gain insights about the processes that govern Abeta peptide deposition. Our results show that pl...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.94.14.7612
更新日期:1997-07-08 00:00:00
abstract::In a medium without Na+, gamma-aminobutyric acid (GABA) binds at 0 degrees to freshly prepared crude synaptic membranes from rat cerebral cortex with an apparent dissociation constant of 218 nM. An endogenous inhibitor of the Na+-independent GABA binding was removed from these membranes by freezing and thawing and by ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.75.8.4024
更新日期:1978-08-01 00:00:00
abstract::l-tryptophan (Trp), an essential amino acid for mammals, is the precursor of a wide array of immunomodulatory metabolites produced by the kynurenine and serotonin pathways. The kynurenine pathway is a paramount source of several immunoregulatory metabolites, including l-kynurenine (Kyn), the main product of indoleamin...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1918215117
更新日期:2020-02-18 00:00:00
abstract::Pancreatic ductal adenocarcinoma (PDAC) is characterized by the presence of abundant desmoplastic stroma primarily composed of cancer-associated fibroblasts (CAFs). It is generally accepted that CAFs stimulate tumor progression and might be implicated in drug resistance and immunosuppression. Here, we have compared th...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1717802115
更新日期:2018-02-06 00:00:00
abstract::Nuclear receptor SET domain containing protein 2 (NSD2) catalyzes the methylation of histone H3 lysine 36 (H3K36). It is a determinant in Wolf-Hirschhorn syndrome and is overexpressed in human multiple myeloma. Despite the relevance of NSD2 to cancer, there are no potent, selective inhibitors of this enzyme reported. ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1521036113
更新日期:2016-02-02 00:00:00
abstract::Sex determination in mammals is governed by antagonistic interactions of two genetic pathways, imbalance in which may lead to disorders/differences of sex development (DSD) in human. Among 46,XX individuals with testicular DSD (TDSD) or ovotesticular DSD (OTDSD), testicular tissue is present in the gonad. Although the...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1921676117
更新日期:2020-06-16 00:00:00
abstract::Chromatin insulators or boundaries are proposed to structure the chromatin fiber into functionally independent domains by promoting the formation of chromatin loops. These elements can block the communication between an enhancer and a gene when placed between them. Interestingly, it has been previously observed that t...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0403959101
更新日期:2004-10-12 00:00:00
abstract::The PsaF-deficient mutant 3bF of Chlamydomonas reinhardtii was used to modify PsaF by nuclear transformation and site-directed mutagenesis. Four lysine residues in the N-terminal domain of PsaF, which have been postulated to form the positively charged face of a putative amphipathic alpha-helical structure were altere...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.95.13.7339
更新日期:1998-06-23 00:00:00
abstract::We have measured the oxygen concentration in the body water of murine FSa and NFSa fibrosarcomas using a new method for quantitative oxygen concentration determination deep in the tissues of a living animal. The measurement uses unusually low-frequency electron paramagnetic spectroscopy sensitive to substrate 7 cm dee...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.91.26.13047
更新日期:1994-12-20 00:00:00
abstract::Interleukin 1 (IL-1) and tumor necrosis factor alpha are thought to contribute to the inflammatory response associated with autoimmune diseases. Transforming growth factor beta 1 (TGF-beta 1) counteracts many effects of these cytokines and has various immunosuppressive properties. In the present study, it is shown tha...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.88.7.2918
更新日期:1991-04-01 00:00:00
abstract::Addition of antisense oligonucleotides to cell cultures has been used to specifically inhibit gene expression. We have investigated the mechanism by which oligonucleotides enter living cells. These compounds are taken up by cells in a saturable, size-dependent manner compatible with receptor-mediated endocytosis. Poly...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.86.10.3474
更新日期:1989-05-01 00:00:00
abstract::BDF1 [(C57BL/6 X DBA/2)F1] mice were primed with alum-absorbed ovalbumin, and their spleen cells were cultured with ovalbumin to activate antigen-primed T cells. The activated T cells were then propagated in interleukin 2-containing medium in the presence or absence of affinity-purified glycosylation-inhibiting factor...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.84.8.2444
更新日期:1987-04-01 00:00:00
abstract::Measures of complexity derived from ergodic theory of dynamical systems were developed and applied to an exemplary data set describing locomotor movements of rats in a bounded space. A symbolic dynamical system was obtained by partitioning the event space into equally probable partition elements, using a k-dimensional...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.87.2.723
更新日期:1990-01-01 00:00:00
abstract::Mycobacterium abscessus (Mabs) is a rapidly growing Mycobacterium and an emerging pathogen in humans. Transitioning from a smooth (S) high-glycopeptidolipid (GPL) producer to a rough (R) low-GPL producer is associated with increased virulence in zebrafish, which involves the formation of massive serpentine cords, absc...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1605477113
更新日期:2016-07-19 00:00:00
abstract::The plasma membrane (PM) is composed of heterogeneous subdomains, characterized by differences in protein and lipid composition. PM receptors can be dynamically sorted into membrane domains to underpin signaling in response to extracellular stimuli. In plants, the plasmodesmal PM is a discrete microdomain that hosts s...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1907799117
更新日期:2020-04-28 00:00:00
abstract::A model of protein-ligand binding kinetics, in which slow solvent dynamics results from hydrophobic drying transitions, is investigated. Molecular dynamics simulations show that solvent in the receptor pocket can fluctuate between wet and dry states with lifetimes in each state that are long enough for the extraction ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1312529110
更新日期:2013-08-13 00:00:00