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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nonhomologous end joining (NHEJ) is a major pathway in multicellular eukaryotes for repairing double-strand DNA breaks (DSBs). Here, the NHEJ reactions have been reconstituted in vitro by using purified Ku, DNA-PK(cs), Artemis, and XRCC4:DNA ligase IV proteins to join incompatible ends to yield diverse junctions. Purified DNA polymerase (pol) X family members (pol mu, pol lambda, and TdT, but not pol beta) contribute to junctional additions in ways that are consistent with corresponding data from genetic knockout mice. The pol lambda and pol mu contributions require their BRCT domains and are both physically and functionally dependent on Ku. This indicates a specific biochemical function for Ku in NHEJ at incompatible DNA ends. The XRCC4:DNA ligase IV complex is able to ligate one strand that has only minimal base pairing with the antiparallel strand. This important aspect of the ligation leads to an iterative strand-processing model for the steps of NHEJ.
Mol Cell 2004 Dec 03
PMID:A biochemically defined system for mammalian nonhomologous DNA end joining. 1557 26

The pathogenesis of reexpansion pulmonary edema is not yet fully understood. We therefore studied its mechanism in a rat model in which the left lung was collapsed by bronchial occlusion for 1 h and then reexpanded and ventilated for an additional 3 h. We then evaluated the production of reactive oxygen species in the lungs using fluorescent imaging and cerium deposition electron microscopic techniques and the incidence of apoptosis using the TdT-mediated dUTP-digoxigenin nick end labeling (TUNEL) method. We found that pulmonary reexpansion induced production of reactive oxygen species and then apoptosis, mainly in endothelial and alveolar type II epithelial cells. Endothelial cells and alveolar type I and II epithelial cells in the reexpanded lung were positive for TUNEL and cleaved caspase-3. DNA fragmentation was also observed in the reexpanded lung. In addition, wet-dry ratios obtained with reexpanded lungs were significantly higher than those obtained with control lungs, indicating increased fluid content. All of these effects were attenuated by pretreating rats with a specific xanthine oxidase inhibitor, sodium (-)-8-(3-methoxy-4-phenylsulfinylphenyl) pyrazolo[1,5-a]-1,3,5-triazine-4(1H)-one. It thus appears that pulmonary reexpansion activates xanthine oxidase in both endothelial and alveolar type II epithelial cells and that the reactive oxygen species produced by the enzyme induce apoptosis among the endothelial and alveolar type I and II epithelial cells that make up the pulmonary water-air barrier, leading to reexpansion pulmonary edema.
Am J Physiol Lung Cell Mol Physiol 2005 Sep
PMID:Pulmonary reexpansion causes xanthine oxidase-induced apoptosis in rat lung. 1587 59

The possible antiproliferative and apoptotic inducing potentials of fresh juice prepared from Scutellaria barbata (SBJ) and warmed water extract of Radix Sophorae Tonkinensis (RSTE) have been tested on a series of cancer cell lines, including HepG2 hepatoblastoma, Hep3B hepatocellular carcinoma, MDA-MB231 breast carcinoma, A549 lung cancer and KG-1 acute myelogenous leukaemia in vitro. Both SBJ and RSTE were able to inhibit the growth of cancer cell lines and induce apoptosis. Further analysis of the action of RSTE on HepG2 cells suggested that the activity of the central machinery of apoptosis, caspase 3, was significantly elevated. Oligo-nucleosomal length DNA fragments formation was readily detected by TdT-mediated dUTP nick end labelling assay after RSTE treatment. Taken together, we believe that, although Radix Sophorae Tonkinensis was demonstrated to have toxic components including matrine and oxymatrine, it is still worthwhile to further investigate its anti-cancer potential under a safety toxicological precaution.
Int J Mol Med 2005 Aug
PMID:Activities of fresh juice of Scutellaria barbata and warmed water extract of Radix Sophorae Tonkinensis on anti-proliferation and apoptosis of human cancer cell lines. 1601 72

At least three DNA polymerases participate in nonhomologous end joining in mammalian cells: pol mu, pol kappa, and TdT. A study in this issue of Molecular Cell (Nick McElhinny et al., 2005) clarifies the role of pol mu in end joining at the kappa light chain locus and also provides a biochemical explanation for the unique polymerization functions of pol mu on DNA ends.
Mol Cell 2005 Aug 05
PMID:Saving the ends for last: the role of pol mu in DNA end joining. 1606 Nov 82

Three Pol X family members have been linked to nonhomologous end joining (NHEJ) in mammals. Template-independent TdT promotes diversity during NHEJ-dependent repair of V(D)J recombination intermediates, but the roles of the template-dependent polymerases mu and lambda in NHEJ remain unclear. We show here that pol mu and pol lambda are similarly recruited by NHEJ factors to fill gaps when ends have partially complementary overhangs, suggesting equivalent roles promoting accuracy in NHEJ. However, only pol mu promotes accuracy during immunoglobulin kappa recombination. This distinctive in vivo role correlates with the TdT-like ability of pol mu, but not pol lambda, to act when primer termini lack complementary bases in the template strand. However, unlike TdT, synthesis by pol mu in this context is primarily instructed by a template from another DNA molecule. This apparent gradient of template dependence is largely attributable to a small structural element that is present but different in all three polymerases.
Mol Cell 2005 Aug 05
PMID:A gradient of template dependence defines distinct biological roles for family X polymerases in nonhomologous end joining. 1606 Nov 76

Transgenic (TG) human (h) extracellular superoxide dismutase (EC-SOD) targeted to type II cells protects postnatal newborn mouse lung development against hyperoxia by unknown mechanisms. Because alveolar development depends on timely proliferation of type II epithelium and differentiation to type I epithelium, we measured proliferation in bronchiolar and alveolar (surfactant protein C-positive) epithelium in air and 95% O2-exposed wild-type (WT) and TG hEC-SOD newborn mice at postnatal days 3, 5, and 7 (P3-P7), traversing the transition from saccular to alveolar stages. We found that TG hEC-SOD ameliorated the 95% O2-impaired bromodeoxyuridine uptake in alveolar and bronchiolar epithelium at P3, but not at P5 and P7, when overall epithelial proliferation rates were lower in air-exposed WT mice. Mouse EC-, CuZn-, and Mn-SOD expression were unaffected by hyperoxia or genotype. TG mice had less DNA damage than 95% O2-exposed WT mice at P3, measured by TdT-mediated dUTP nick end labeling (P < 0.05). Hyperoxia induced cell-cycle inhibitory protein p21cip/waf mRNA at P3, WT > TG, P = 0.06. 95% O2 impaired apical expression of type I cell alpha protein (T1alpha) in WT but not in TG mice at P3 and increased T1alpha in WT and TG mice at P7. Reducing the 95% O2-induced impairment of epithelial proliferation at a critical window of lung development was associated with protection against DNA damage and preservation of apical T1alpha expression at P3.
Am J Physiol Lung Cell Mol Physiol 2006 Jan
PMID:Transgenic extracellular superoxide dismutase protects postnatal alveolar epithelial proliferation and development during hyperoxia. 1610 Feb 89

We have recently demonstrated the antiproliferative and apoptotic activities of herbal traditional Chinese medicines, including the analomous fruit extract of Gleditsia sinensis, the fresh juice of Scutellaria barbata and the warmed water extract of Radix Sophorae Tonkinensis on a series of human carcinoma cells. Here, we further report the potential anti-cancer activity of the warmed water extract of Brucea javanica (BJE). Four cancer cell lines, including A549 non-small cell lung cancer, Hep3B hepatocellular carcinoma, MDA-MB231 breast cancer and SLMT-1 oesophageal squamous cell carcinoma, were incubated with BJE and strong apoptotic induction was observed under inverted microscopic investigation for all of the four cell lines tested. Using the MDA-MB231 breast cancer cell line as an experimental model, additional analyses supported the hypothesis that the mitochondrial membrane potential depolarization pathway was induced by BJE. The APO-1/Fas receptor death induction pathway was not activated under the influence of BJE, as studied by staining with Fas ligand and Fas receptor specific antibodies. Accordingly, only weak activation of caspase 8 was observed upon BJE treatment. On the other hand, caspase 3 activity was stimulated up to five-fold in BJE-treated cells compared to untreated controls. Oligonucleosomal DNA fragmentation formation was detected by labelling the nucleic acid ladders with TdT-mediated dUTP nick end labelling. Collectively, BJE-induced cancer cell death proceeds through a mitochondrial dependent pathway associated with caspase 3 activation.
Int J Mol Med 2005 Dec
PMID:Antiproliferative and apoptosis-inducing activity of Brucea javanica extract on human carcinoma cells. 1627

This study aims to assess the distribution of lymphoma subtypes in Shanxi, China, according to the World Health Organization (WHO) classification, and to compare the relative distribution with other areas of the world. H&E-stained tissue sections from the archives of the Shanxi Tumor Hospital, China, were reviewed and 447 cases with sufficient materials were selected for detailed study. A panel of antibodies and probes was assembled, including antibodies to ALK1, bcl-6, CDs 1alpha, 3, 4, 5, 7, 8, 10, 15, 20, 23, 30, 43, 56, 68, 79alpha, and 99, cyclin D1, EMA, kappa, lambda, LMP1, PAX5, TdT, Vs38C and ZAP70, plus EBER RNA probe by in situ hybridization. The 447 lymphoma cases, subtyped according to the WHO classification, were assembled in triplicate into 11 tissue microarrays and examined with the panel of markers described. Among the 447 cases, 385 (82.6%) were confirmed to be non-Hodgkin lymphomas (NHL) and 62 (13.9%) were Hodgkin lymphomas of classic type (CHL). Of the NHL cases, 68.6% were B-cell lymphomas and 30.6% T/NK-cell lymphomas. Histiocytic neoplasms accounted for only three cases (0.8%). Diffuse large B-cell lymphomas (DLBCL) were the most common subtype (35.1%), followed by peripheral T-cell lymphomas unspecified (PTun, 12.0%), extranodal marginal zone B-cell lymphomas (MALT lymphomas, 11.7%), follicular lymphomas (FL, 8.6%), T-lymphoblastic lymphomas (T-LBL, 7.0%), anaplastic large cell lymphomas (ALCL, 4.2%), B small lymphocytic lymphomas (B SLL, 3.6%), and mantle cell lymphomas (MCL, 2.6%). Of 263 B-cell neoplasms, 105 (39.9%) expressed immunoglobulin light chain, including 52 kappa and 53 lambda, detectable in paraffin sections. The incidence of DLBCL was similar to many Western countries and Asia. The frequency of FL was, however, much lower than the usual pattern in Western countries, although NK/T-cell lymphomas were more common (30.6%), similar to other countries in Asia, including Japan and Korea. With regard to markers of EBV infection, 8 of 385 (2.1%) NHL cases gave positive findings by both in situ hybridization (EBER RNA) and immunohistochemistry (LMP-1), whereas 24 (6.2%) expressed only the EBER and 12 (3.1%) expressed only LMP-1. EBV positivity was found in 24 of 119 (20.2%) T and NK cell lymphomas, in 20 of 263 (7.6%) B cell neoplasms, and in 37 of 62 (59.7%) CHLs. In CHLs there was complete concordance of results by both in situ hybridization (EBER RNA) and immunohistochemistry (LMP-1) procedures. ZAP70 was detected in most T cell-lineage disorders (61.4%) and also in a subset of B small lymphocytic lymphomas (50%). However, ZAP-70 was expressed in a minority of other types of B-cell lymphomas, including precursor B-cell acute lymphoblastic leukemia (25%), diffuse large B-cell lymphoma (26.7%), follicular lymphoma (15.2%), and lymphoplasmacytic lymphoma (9.1%). Immunohistochemical analysis represents an effective method for assessing ZAP-70 expression and reveals that a variety of B-cell malignant neoplasms express ZAP-70, albeit at low frequency.
Appl Immunohistochem Mol Morphol 2005 Dec
PMID:Distribution and ZAP-70 expression of WHO lymphoma categories in Shanxi, China: a review of 447 cases using a tissue microarray technique. 1628 Jun 61

In this study, C57BL/6J mice were exposed to hyperoxia and allowed to recover in room air. The sublethal dose of hyperoxia for C57BL/6J was 48 h. Distal lung cellular isolates from treated animals were characterized as 98% epithelial, with minor fibroblast and endothelial cell contaminants. Cells were then verified as 95% pure alveolar epithelial type II cells (AEC2) by surfactant protein C (SP-C) expression. After hyperoxia exposure in vivo, fresh, uncultured AEC2 were analyzed for proliferation by cell yield, cell cycle, PCNA expression, and telomerase activity. DNA damage was assessed by TdT-dUTP nick-end labeling, whereas induction of DNA repair was evaluated by GADD-153 expression. A baseline level for proliferation and damage was observed in cells from control animals that did not alter significantly during acute hyperoxia exposure. However, a rise in these markers was observed 24 h into recovery. Over 72 h of recovery, markers for proliferation remained elevated, whereas those for DNA damage and repair peaked at 48 h and then returned back to baseline. The expression of GADD-153 followed a distinct course, rising significantly during acute exposure and peaking at 48 h recovery. These data demonstrate that in healthy, adult male C57BL/6J mice, AEC2 proliferation, damage, and repair follow separate courses during hyperoxia recovery and that both proliferation and efficient repair may be required to ensure AEC2 survival.
Am J Physiol Lung Cell Mol Physiol 2006 Apr
PMID:Contribution of proliferation and DNA damage repair to alveolar epithelial type 2 cell recovery from hyperoxia. 1629 57

Cantharidin isolated from Mylabris caraganae and other insects has been used as an anti-cancer drug in China for many years. However, its toxicity on the renal system and suppression effect on bone marrow limits its usage clinically. Based on the core structure of cantharidin, we have chemically synthesized two cantharidin analogues (compounds 2 and 3). The cytotoxic activity of these analogues was demonstrated on the Hep3B hepatocellular carcinoma, MDA-MB231 breast cancer, A549 non-small cell lung carcinoma and KG1a acute myelogenous leukaemia (AML) cell lines by monitoring the intracellular adenosine triphosphate level. Morphological changes in these cancer cell lines, including cell shrinkage and loss of adherent potential, were readily observed. By making use of the KG1a AML cells as a test model, we further found that mitochondrial membrane potential depolarization and reduction of intracellular bcl-2 anti-apoptotic protein level were involved. These resulted in the activation of caspase 3 protease activity and oligonucleosomal length DNA fragment formation as detected by both time resolved fluorescence technology-based caspase activity assay and TdT-mediated dUTP nick end-labelling assay.
Int J Mol Med 2006 Jan
PMID:Induction of apoptosis on carcinoma cells by two synthetic cantharidin analogues. 1632 24


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