Abstract：
:PARP-1 is a nuclear protein that has important roles in maintenance of genomic integrity. During genotoxic stress, PARP-1 recruits to sites of DNA damage where PARP-1 domain architecture initiates catalytic activation and subsequent poly(ADP-ribose)-dependent DNA repair. PARP-1 inhibition is a promising new way to selectively target cancers harboring DNA repair deficiencies. However, current inhibitors target other PARPs, raising important questions about long-term off-target effects. Here, we propose a new strategy that targets PARP-1 allosteric regulation as a selective way of inhibiting PARP-1. We found that disruption of PARP-1 domain-domain contacts through mutagenesis held no cellular consequences on recruitment to DNA damage or a model system of transcriptional regulation, but prevented DNA-damage-dependent catalytic activation. Furthermore, PARP-1 mutant overexpression in a pancreatic cancer cell line (MIA PaCa-2) increased sensitivity to platinum-based anticancer agents. These results not only highlight the potential of a synergistic drug combination of allosteric PARP inhibitors with DNA-damaging agents in genomically unstable cancer cells (regardless of homologous recombination status), but also signify important applications of selective PARP-1 inhibition. Finally, the development of a high-throughput PARP-1 assay is described as a tool to promote discovery of novel PARP-1 selective inhibitors.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Steffen JD,Tholey RM,Langelier MF,Planck JL,Schiewer MJ,Lal S,Bildzukewicz NA,Yeo CJ,Knudsen KE,Brody JR,Pascal JMdoi
10.1158/0008-5472.CAN-13-1701subject
Has Abstractpub_date
2014-01-01 00:00:00pages
31-7issue
1eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-13-1701journal_volume
74pub_type
杂志文章相关文献
CANCER RESEARCH文献大全abstract：:Mice lacking N-acetylglucosaminyltransferase III (GlcNAc-TIII) exhibit slightly but significantly retarded liver tumor progression after a single injection of 10 micro g/g diethylnitrosamine (DEN) and continued administration of phenobarbital (PB) in drinking water. A key question is whether the absence of GlcNAc-TIII...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2003-11-15 00:00:00
abstract：:The breast- and ovarian-specific tumor suppressor BRCA1 has been implicated in numerous cellular processes, including transcription, ubiquitination, and DNA repair. Its tumor suppression activity is tightly linked to that of BARD1, a protein that heterodimerizes with BRCA1. It has been previously shown that BRCA1 bind...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-05-3296
更新日期：2006-02-15 00:00:00
abstract：:Mutated ras genes are powerful transforming agents in vitro and are found in a wide variety of human tumors in vivo. We characterized the histopathology and p21 protein expression associated with tumorigenesis in line 69 transgenic mice carrying an activated, human c-Ha-ras gene on the Y-chromosome (A. C. Andres, C. A...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1991-07-15 00:00:00
abstract：:We investigated the potential role of mitochondrial manganese superoxide dismutase (Mn-SOD) in protective activity against irradiation by analyzing cell viability by a colony formation assay and by detecting apoptosis in stably human Mn-SOD gene-transfected HLE, a hepatocellular carcinoma cell line. We found that over...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2001-07-15 00:00:00
abstract：:We previously reported that bone marrows of breast cancer patients contained tumor antigen-specific CD8(+) T cells with central or effector memory phenotype. Using a recently developed ret transgenic mouse melanoma model, we now show that bone marrows and tumors of transgenic mice contain high frequencies of CD8(+) T ...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-08-1464
更新日期：2008-11-15 00:00:00
abstract：:The intention of this study was to estimate the pharmacological advantage of a clinically applicable method of isolated liver perfusion (ILP) over hepatic artery infusion (HAI) administering various doses of 5-fluorouracil (FUra). FUra concentrations were measured using high-performance liquid chromatography in liver ...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1991-03-15 00:00:00
abstract：:Comparison of the cell surface characteristics of the parental strain-specific TA3-St ascites cell (I) of the strain A mouse and the more allotransplantable TA3-St/ticol ascites cell (II), immunoselected for reduced absorption of anti-H-2a antibody from Cell I, revealed the following. Cell II, like Cell I, possessed n...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1983-09-01 00:00:00
abstract：:A direct ligand-banding radioassay for methotrexate (MTX) has been developed using dihydrofolate reductase, contained in the lysate of L1210 leukemia cells, as the binding determinant. The procedure is a two-phase reaction system where standard MTX concentrations or the sample being assayed in incubated with the reage...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1975-08-01 00:00:00
abstract：:In solid tumors, cancer cells subjected to ischemic conditions trigger distinct signaling pathways contributing to angiogenic stimulation and tumor development. Characteristic features of tumor ischemia include hypoxia and glucose deprivation, leading to the activation of hypoxia-inducible factor-1-dependent signaling...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-06-3235
更新日期：2007-07-15 00:00:00
abstract：:Although more than 100 different BRCA1 germ-line mutations have already been identified in breast and/or ovarian cancer families, we report for the first time a deleterious genomic rearrangement in BRCA1. A 1-kb deletion comprising exon 17 was found in a large breast and ovarian cancer family, leading to a frameshift ...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1997-03-01 00:00:00
abstract：:15-Lipoxygenase (15-LOX)-2 is expressed in benign prostate secretory cells and benign prostate produces 15S-hydroxyeicosatetraenoic acid (15S-HETE) from exogenous arachidonic acid (AA). In contrast, 15S-LOX-2 and 15S-HETE formation are reduced in prostate carcinoma (Pca). The mechanisms whereby reduced 15-LOX-2 may co...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2001-01-15 00:00:00
abstract：:A common form of multidrug resistance in human cancer results from expression of the MDR1 gene which encodes a plasma membrane energy-dependent multidrug efflux pump. We have engineered transgenic mice which express this multidrug transporter in their bone marrow cells and demonstrated that peripheral WBC of these ani...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1991-10-01 00:00:00
abstract：:Malignant pleural mesothelioma is a relatively uncommon and yet incurable tumor. The pathogenesis of mesothelioma remains poorly understood. This study evaluated the role of Wnt signaling in mesothelioma. Western blot analysis was conducted to confirm the expression of Dishevelled (Dvl) and cytosolic beta-catenin in m...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2003-08-01 00:00:00
abstract：:The effect of commercial saccharin preparations on urethan-induced mouse lung tumorigenesis was assessed by gavaging groups of male strain A mice with 1-g/kg doses of each saccharin preparation on a daily basis 5 days/week. Gavage was initiated 1 week before i.p. injection of either a low (0.1 mg/g) or a high (1 mg/g)...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1980-11-01 00:00:00
abstract：:Activation of activator protein 1 (AP-1) and nuclear factor kappaB (NFkappaB)-dependent transcription is required for tumor promotion in cell culture models and transgenic mice. Dominant-negative c-Jun (TAM67) blocks AP-1 activation by dimerizing with Jun or Fos family proteins and blocks NFkappaB activation by intera...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-06-0522
更新日期：2007-03-15 00:00:00
abstract：:Morphine is used to treat pain in several medical conditions including cancer. Here we show that morphine, in a concentration typical of that observed in patients' blood, stimulates human microvascular endothelial cell proliferation and angiogenesis in vitro and in vivo. It does so by activating mitogen-activated prot...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2002-08-01 00:00:00
abstract：:alpha-Difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase (ODC), was used to select two very highly drug-resistant cell lines, designated K562-DFMOr and V79-DFMOr. Both DFMO-resistant cell lines exhibited elevated ODC expression due to gene amplification. Moreover, the...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1993-11-01 00:00:00
abstract：:Although peptide immunization often leads to the induction of strong T-cell responses, it is seldom effective against established tumors. One possibility is that these T-cell responses are not strong enough or do not last sufficiently long to have an effect in tumor eradication. Here, we examined the role of synthetic...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2003-06-15 00:00:00
abstract：:Pheochromocytomas are tumors originating from chromaffin cells, the large majority of which are sporadic neoplasms. The genetic and molecular events determining their tumorigenesis continue to remain unknown. On the other hand, RET germ-line mutations cause the inheritance of familial tumors in multiple endocrine neop...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2000-03-01 00:00:00
abstract：:2-Phenyl-1,2-benzisoselenazol-3(2H)-one (ebselen) is classified as a relatively nontoxic selenium compound, probably because of its bound selenium moiety. In thiol-rich tissues, such as the kidneys, ebselen is converted into selenol intermediates. Selenols are nucleophilic agents which might be able to react with plat...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1990-11-01 00:00:00
abstract：:Histone demethylase LSD1 (also known as KDM1 and AOF2) is active in various cancer cells, but its biological significance in human carcinogenesis is unexplored. In this study, we explored hypothesized interactions between LSD1 and MYPT1, a known regulator of RB1 phosphorylation. We found that MYPT1 was methylated in v...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-10-2446
更新日期：2011-02-01 00:00:00
abstract：:Apoptosis is a mode of cell death that is carefully regulated based on cellular and environmental signals. The ability to modulate the individual cellular machinery and thereby to promote apoptosis is an important strategy in cancer therapy. It has previously been shown that overexpression of the transcription factor ...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1997-11-01 00:00:00
abstract：:The role of hereditary polymorphisms of the arylamine N-acetyltransferase 1 (NAT1) gene in the etiology of urinary bladder cancer is controversial. NAT1 is expressed in the urothelium and may O-acetylate hydroxyl amines, particularly in subjects with low NAT2 activity. Thus, NAT1 polymorphisms may affect the individua...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2001-07-01 00:00:00
abstract：:We investigated the relationship between DNA cytosine methylation and the expression of two genes associated with resistance to DNA methylation damage. Variants of RajiMex- cells acquired resistance to N-methyl-N-nitrosourea by either reactivating a previously silent O6-methylguanine-DNA methyltransferase (MGMT) gene ...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2000-06-15 00:00:00
abstract：:Galectin-1 (Gal1), an evolutionarily conserved glycan-binding protein, contributes to the creation of an immunosuppressed microenvironment at sites of tumor growth. In spite of considerable progress in elucidating its role in tumor-immune escape, the mechanisms underlying the inhibitory functions of Gal1 remain obscur...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-12-2418
更新日期：2013-02-01 00:00:00
abstract：:Oligodendrogliomas are a specific subtype of brain tumor of which the majority responds favorably to chemotherapy. In this study, we made use of expression profiling to identify chemosensitive oligodendroglial tumors. Correlation of expression profiles to loss of heterozygosity on 1p and 19q, common chromosomal aberra...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-05-1886
更新日期：2005-12-15 00:00:00
abstract：:The INK4a/ARF locus encodes two distinct tumor suppressors, p16INK4a and p14ARF. Although the contribution of p16INK4a to human tumorigenesis through point mutation, deletion, and hypermethylation has been widely documented, little is known about specific p14ARF lesions and their consequences. Recent data indicate tha...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2001-04-01 00:00:00
abstract：:Metastasis is the primary cause of death from breast cancer. A xenograft model was used to identify genes potentially involved with metastasis, comparing expression in the poorly metastatic GI101A human breast cancer cell line and a highly metastatic variant, GILM2. cDNA microarray analyses of these isogenic variants ...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-05-0108
更新日期：2005-07-01 00:00:00
abstract：:The effects on Leydig cell tumorigenesis of surgical cryptorchidy, parabiotic union with a castrate male partner, and a combination on the two procedures as well as of the continuous exposure to a high level of diethylstilbestrol stimulation were studied in the high-tumor Fischer rat. Localized foci of adenomatous hyp...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1981-08-01 00:00:00
abstract：:Tumor cell-derived selectin ligands mediate contact to the endothelium, platelets, and leukocytes through binding to selectins that facilitates metastasis. Here, we describe the mechanism of how endogenous (non-tumor derived) selectin ligands contribute to metastasis using α(1,3)fucosyltransferase 7 (Fuc-TVII(-/-))-de...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-13-0946
更新日期：2014-02-01 00:00:00
