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411.
Roberto R. Rosato Sarah S. Kolla Stefanie K. Hock Jorge A. Almenara Ankita Patel Sanjay Amin Peter Atadja Paul B. Fisher Paul Dent Steven Grant 《The Journal of biological chemistry》2010,285(13):10064-10077
Mechanisms underlying histone deacetylase inhibitor (HDACI)-mediated NF-κB activation were investigated in human leukemia cells. Exposure of U937 and other leukemia cells to LBH-589 induced reactive oxygen species (ROS) followed by single strand (XRCC1) and double strand (γ-H2AX) DNA breaks. Notably, LBH-589 lethality was markedly attenuated by small interfering RNA (siRNA) knockdown of the DNA damage-linked histone, H1.2. LBH-589 triggered p65/RelA activation, NF-κB-dependent induction of Mn-SOD2, and ROS elimination. Interference with LBH-589-mediated NF-κB activation (e.g. in IκBα super-repressor transfected cells) diminished HDACI-mediated Mn-SOD2 induction and increased ROS accumulation, DNA damage, and apoptosis. The Mn-SOD2 mimetic TBAP (manganese(III)-tetrakis 4-benzoic acid porphyrin) prevented HDACI-induced ROS and NF-κB activation while dramatically attenuating DNA damage and cell death. In contrast, TRAF2 siRNA knockdown, targeting receptor-mediated NF-κB activation, blocked TNFα- but not HDACI-mediated NF-κB activation and lethality. Consistent with ROS-mediated DNA damage, LBH-589 exposure activated ATM (on serine 1981) and increased its association with NEMO. Significantly, siRNA NEMO or ATM knockdown blocked HDACI-mediated NF-κB activation, resulting in diminished MnSOD2 induction and enhanced oxidative DNA damage and cell death. In accord with the recently described DNA damage/ATM/NEMO pathway, SUMOylation site mutant NEMO (K277A or K309A) cells exposed to LBH-589 displayed diminished ATM/NEMO association, NEMO and p65/RelA nuclear localization/activation, and MnSOD2 up-regulation. These events were accompanied by increased ROS production, γ-H2AX formation, and cell death. Together, these findings indicate that in human leukemia cells, HDACIs activate the cytoprotective NF-κB pathway through an ATM/NEMO/SUMOylation-dependent process involving the induction of ROS and DNA damage and suggest that blocking NF-κB activation via the atypical ATM/NEMO nuclear pathway can enhance HDACI antileukemic activity. 相似文献
412.
Sarah G Rees Janet R Davies Debbie Tudor Carl R Flannery Clare E Hughes Colin M Dent Bruce Caterson 《Matrix biology》2002,21(7):593-602
Cartilage superficial zone protein/proteoglycan (SZP) or proteoglycan 4 (PRG4), has been demonstrated to have the potential for several distinct biological functions including cytoprotection, lubrication and matrix binding. In the present study, we have examined both the immunolocalisation and the mRNA expression pattern of PRG4 in tissue harvested from the compressed and tensional regions of young and mature bovine tendons. Immunohistochemical analyses, utilizing monoclonal antibody 3-A-4 which recognizes a conformational-dependent epitope on native PRG4, demonstrated that PRG4 is present predominantly at the surface of fibrocartilaginous regions of tendon, with the intensity of immunoreactivity in this region increasing with age. RT-PCR analyses revealed that the expression of PRG4 mRNA can be modulated by exposure to cytokines and growth factors. In addition, analyses of human pathological tendon revealed that PRG4 may also be expressed as an alternatively spliced form lacking exons which encode part of the N-terminal matrix-binding and cell-proliferative domain; however, it remains to be determined whether such splice variants are a feature of human tendon, regardless of disease state. Taken together, these data indicate that PRG4 may play an important cytoprotective role by preventing cellular adhesion to the tendon surface as well as providing lubrication during normal tendon function, in a manner complimentary to cartilage PRG4. Structural modifications to SZP, together with a reduction in synthesis during tendon inflammation with injury and disease may account for the formation of tendon adhesions and contribute to the overall dysfunction of the tissue. 相似文献
413.
With the cancellation of fenamiphos in the near future, alternative nematode management tactics for plant-parasitic nematodes (PPN) on golf courses need to be identified. The use of entomopathogenic nematodes (EPN) has been suggested as one possible alternative. This paper presents the results of 10 experiments evaluating the efficacy of EPN at managing PPN on turfgrasses and improving turf performance. These experiments were conducted at various locations throughout Florida over the course of a decade. In different experiments, different EPN species were tested against different species of PPN. Separate experiments evaluated multiple rates and applications of EPN, compared different EPN species, and compared single EPN species against multiple species of PPN. In a few trials, EPN were associated with reductions in certain plant-parasite species, but in other trials were associated with increases. In most trials, EPN had no effect on plant parasites. Because EPN were so inconsistent in their results, we conclude that EPN are not acceptable alternatives to fenamiphos by most turf managers in Florida at this time. 相似文献
414.
SUN1 interacts with nuclear lamin A and cytoplasmic nesprins to provide a physical connection between the nuclear lamina and the cytoskeleton 总被引:2,自引:0,他引:2 下载免费PDF全文
Haque F Lloyd DJ Smallwood DT Dent CL Shanahan CM Fry AM Trembath RC Shackleton S 《Molecular and cellular biology》2006,26(10):3738-3751
Nuclear migration and positioning within cells are critical for many developmental processes and are governed by the cytoskeletal network. Although mechanisms of nuclear-cytoskeletal attachment are unclear, growing evidence links a novel family of nuclear envelope (NE) proteins that share a conserved C-terminal SUN (Sad1/UNC-84 homology) domain. Analysis of Caenorhabditis elegans mutants has implicated UNC-84 in actin-mediated nuclear positioning by regulating NE anchoring of a giant actin-binding protein, ANC-1. Here, we report the identification of SUN1 as a lamin A-binding protein in a yeast two-hybrid screen. We demonstrate that SUN1 is an integral membrane protein located at the inner nuclear membrane. While the N-terminal domain of SUN1 is responsible for detergent-resistant association with the nuclear lamina and lamin A binding, lamin A/C expression is not required for SUN1 NE localization. Furthermore, SUN1 does not interact with type B lamins, suggesting that NE localization is ensured by binding to an additional nuclear component(s), most likely chromatin. Importantly, we find that the luminal C-terminal domain of SUN1 interacts with the mammalian ANC-1 homologs nesprins 1 and 2 via their conserved KASH domain. Our data provide evidence of a physical nuclear-cytoskeletal connection that is likely to be a key mechanism in nuclear-cytoplasmic communication and regulation of nuclear position. 相似文献
415.
Gwinn WM Damsker JM Falahati R Okwumabua I Kelly-Welch A Keegan AD Vanpouille C Lee JJ Dent LA Leitenberg D Bukrinsky MI Constant SL 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(7):4870-4879
Extracellular cyclophilins have been well described as chemotactic factors for various leukocyte subsets. This chemotactic capacity is dependent upon interaction of cyclophilins with the cell surface signaling receptor CD147. Elevated levels of extracellular cyclophilins have been documented in several inflammatory diseases. We propose that extracellular cyclophilins, via interaction with CD147, may contribute to the recruitment of leukocytes from the periphery into tissues during inflammatory responses. In this study, we examined whether extracellular cyclophilin-CD147 interactions might influence leukocyte recruitment in the inflammatory disease allergic asthma. Using a mouse model of asthmatic inflammation, we show that 1) extracellular cyclophilins are elevated in the airways of asthmatic mice; 2) mouse eosinophils and CD4+ T cells express CD147, which is up-regulated on CD4+ T cells upon activation; 3) cyclophilins induce CD147-dependent chemotaxis of activated CD4+ T cells in vitro; 4) in vivo treatment with anti-CD147 mAb significantly reduces (by up to 50%) the accumulation of eosinophils and effector/memory CD4+ T lymphocytes, as well as Ag-specific Th2 cytokine secretion, in lung tissues; and 5) anti-CD147 treatment significantly reduces airway epithelial mucin production and bronchial hyperreactivity to methacholine challenge. These findings provide a novel mechanism whereby asthmatic lung inflammation may be reduced by targeting cyclophilin-CD147 interactions. 相似文献
416.
Using inbreeding theory as applied to neutral alleles inherited maternally,
we generate expected probability distributions of times to identity by
descent for random pairs of mitochondrial genotypes within a population or
within an entire species characterized by high gene flow. For comparisons
with these expectations, empirical distributions of times to most recent
common ancestry were calculated (by conventional mtDNA clock calibrations)
from mtDNA haplotype distances observed within each of three vertebrate
species--American eels, hardhead catfish, and redwinged blackbirds. These
species were chosen for analysis because census population size in each is
currently large and because both genetic and life-history data are
consistent with the postulate that historical gene flow within these
species has been high. The observed molecular distances among mtDNA
lineages were two to three orders of magnitude lower than predicted from
census sizes of breeding females, suggesting that rate of mtDNA evolution
is decelerated in these species and/or that long-term effective population
size is vastly smaller than present-day population size. Several
considerations point to the latter possibility as most likely. The genetic
structure of any species is greatly influenced by historical demography;
even for species that are currently abundant, mtDNA gene lineages appear to
have been channeled through fairly small numbers of ancestors.
相似文献
417.
S. K. Liao P. B. Dent P. B. McCulloch 《In vitro cellular & developmental biology. Plant》1976,12(9):654-657
Summary Early monolayer outgrowths of cells from human cutaneous malignant melanomas mostly derived from metastatic lesions were examined
microscopically. Cells resembling the two dendritic types of melanoma previously described in the established lines could
readily be recognized. Of 22 specimens, 14 consisted of cells with a triangular dendritic morphology, four had both triangular
and elongated dendritic morphology, and one had a cuboidal morphology. The remaining three specimens showed only fibroblastic
outgrowths. It is concluded that cells with a triangular dendritic morphology are either the most common type of the secondary
cutaneous melanomas, or alternately the most adaptable to the present culture conditions. An association of a more favorable
prognosis with the homogeneous triangular dendritic cell type is noted.
This study was supported in part by grants from The Medical Research Council of Canada and The Ontario Cancer Treatment and
Research Foundation. 相似文献
418.
P. B. Dent S. K. Liao P. B. McCulloch M. A. Blajchman J. Macnamara 《Cancer immunology, immunotherapy : CII》1978,3(4):239-246
Summary Seven well-characterized human malignant melanoma cell lines have been evaluated in terms of their reactivity in membrane immunofluorescence tests with sera from 48 patients with melanoma, 23 patients with other forms of cancer and 28 normal controls. There was a significantly greater degree of reactivity of melanoma sera (33.7%) than of sera of normal controls (22.2%) or of sera from patients with other forms of cancer (24.2%). The incidence of strong reactors among the melanoma patients was found to be inversely proportional to the extent of disease in the melanoma patients: Stage I, 54.5%, Stage III, 36.8% and Stage IV, 29.4%. Reactivity against non-melanoma cell lines was similar in the three subject groups and was unaffected by stage of disease in the melanoma patients. No single cell line showed preferential reactivity with melanoma sera. There was an increased overall incidence of reactivity of all three subject groups against non-pigmented cell lines.A-B-0 antigens and heterophile antigens were excluded as a cause of seropositivity. The antigen(s) was trypsin-sensitive and neuraminidase-resistant.These data suggest that long term cultures of human melanoma may contain melanoma-associated antigens which may be useful in the further study and search for melanoma-specific antigens. 相似文献
419.
The presence of antibodies to rubella, cytomegalovirus and Toxoplasma gondii was determined at birth and at 6 months of age in a group of 147 infants with cord serum IgM levels ≥ 19.0 mg/dl and in 92 control infants. Maternal syphilis serology was determined in both groups as well. No significant differences in the prevalence or levels of antibodies to these pathogens were found between the two groups which might have led to the diagnosis of unsuspected intrauterine infection. Persistence of antibodies to 6 months of age was similar in the two groups, indicating that this is not a useful index of intrauterine infection.Analysis of the results yielded the following data on the prevalence of antibodies to the pathogens studied: rubella virus, 90 and 75% seropositivity at birth and 6 months respectively; cytomegalovirus, 65 and 35%; and Toxoplasma gondii, 33% seropositivity at birth. 相似文献
420.
Cord blood immunoglobulin M was measured in 3474 consecutive newborn infants. A group of 147 infants with elevated IgM values (≥19.0 mg./100 ml.) were compared with 92 unselected newborn infants with normal IgM values. One infant with clinically unsuspected congenital rubella was detected in the study group while no cases of intra-uterine infection were found among the controls. A greater proportion of mothers in the study group had a history of viral infection. The study group also contained a larger number of mothers who might be considered to be at greater risk of infection with agents known to cause intra-uterine disease. Follow-up studies at 6 months of age revealed no differences between the two groups aside from an increased incidence of minor motor abnormalities in the study group. While it is recognized that infants with cord blood IgM levels truly in excess of 30 mg./100 ml. may represent a high-risk group with respect to proved or subclinical intra-uterine infection, it is concluded that routine cord blood screening for elevated IgM values is not a high-yield procedure for the detection of intra-uterine infection in our population. 相似文献