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151.
Rapid PIKK-dependent release of Chk1 from chromatin promotes the DNA-damage checkpoint response 总被引:1,自引:0,他引:1
BACKGROUND: Checkpoint signaling pathways are of crucial importance for the maintenance of genomic integrity. Within these pathways, the effector kinase Chk1 plays a central role in mediating cell-cycle arrest in response to DNA damage, and it does so by phosphorylating key cell-cycle regulators. RESULTS: By investigating the subcellular distribution of Chk1 by cell fractionation, we observed that around 20% of it localizes to chromatin during all phases of the cell cycle. Furthermore, we found that in response to DNA damage, Chk1 rapidly dissociates from the chromatin. Significantly, we observed a tight correlation between DNA-damage-induced Chk1 phosphorylation and chromatin dissociation, suggesting that phosphorylated Chk1 does not stably associate with chromatin. Consistent with these events being triggered by active checkpoint signaling, inhibition of the DNA-damage-activated kinases ATR and ATM, or siRNA-mediated downregulation of the DNA-damage mediator proteins Claspin and TopBP1, impaired DNA-damage-induced dissociation of Chk1 from chromatin. Finally, we established that Chk1 phosphorylation occurs at localized sites of DNA damage and that constitutive immobilization of Chk1 on chromatin results in a defective DNA-damage-induced checkpoint arrest. CONCLUSIONS: Chromatin association and dissociation appears to be important for proper Chk1 regulation. We propose that in response to DNA damage, PIKK-dependent checkpoint signaling leads to phosphorylation of chromatin-bound Chk1, resulting in its rapid release from chromatin and facilitating the transmission of DNA-damage signals to downstream targets, thereby promoting efficient cell-cycle arrest. 相似文献
152.
Mark M. Smits Anke M. Herrmann Michael Duane Owen W. Duckworth Steeve Bonneville Liane G. Benning Ulla Lundström 《Fungal Biology Reviews》2009,23(4):122-131
Over recent years, the role of fungi, especially mycorrhizal fungi, in the weathering of rock-forming minerals has been increasingly recognised. Much of our understanding of the effects of fungi on mineral weathering is based on macroscopic studies. However, the ability of fungi to translocate materials, including organic acids and siderophores, to specific areas of a mineral surface leads to significant spatial heterogeneity in the weathering process. Thus, geomycologists are confronted with unique challenges of how to comprehend and quantify such a high degree of diversity and complicated arrays of interactions. Recent advances in experimental and analytical techniques have increased our ability to probe the fungal–mineral interface at the resolution necessary to decouple significant biogeochemical processes. Modern microscopy, spectroscopy, mass spectrometry, wet chemistry, and scattering techniques allow for the selective extraction of physical, chemical, and structural data at the micro- to nano-scale. These techniques offer exciting possibilities to study fungal–mineral interactions at the scale of individual hyphae. In this review, we give an overview of some of these techniques with their characteristics, advantages and limitations, and how they can be used to further our understanding of biotic mineral weathering. 相似文献
153.
Kiesman WF Zhao J Conlon PR Petter RC Jin X Smits G Lutterodt F Sullivan GW Linden J 《Bioorganic & medicinal chemistry》2006,14(11):3654-3661
During the search for second-generation adenosine A(1) receptor antagonist alternatives to the clinical candidate 8-(3-oxa-tricyclo[3.2.1.0(2,4)]oct-6-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (BG9719), we developed a series of novel xanthines substituted with norbornyl-lactones that possessed high binding affinities for adenosine A(1) receptors and in vivo activity. 相似文献
154.
Smits TH Rezzonico F Kamber T Goesmann A Ishimaru CA Stockwell VO Frey JE Duffy B 《Journal of bacteriology》2010,192(24):6486-6487
Pantoea vagans is a Gram-negative enterobacterial plant epiphyte of a broad range of plants. Here we report the 4.89-Mb genome sequence of P. vagans strain C9-1 (formerly Pantoea agglomerans), which is commercially registered for biological control of fire blight, a disease of pear and apple trees caused by Erwinia amylovora. 相似文献
155.
Background: Loss of a child has been associated with elevated mortality rates in parents. Studies that focus on the influence of the child's sex on parental mortality are sparse.Objective: The main objective of the present study was to reevaluate the combined impact of the parents' and child's sex within a larger sample and focus on adverse health effects as an objective measure of possible long-term effects of maladaptive grief reactions.Methods: For the time period between 1980 and 1996, all children in Denmark who died before 18 years of age were identified. Parents who had lost a child were identified as the bereaved (exposed) group. Mortality rates of parents within the same-sex parent-child dyad were compared with mortality rates of parents within the opposite-sex parent-child dyad. Separate analyses were performed for bereaved fathers and for bereaved mothers, and additional analyses were conducted to examine the sole effect of the child's sex, irrespective of parental gender. A Cox proportional hazards regression model was used to estimate the hazard ratios (HRs) with 95% CIs.Results: The study population consisted of 21,062 parents (mean age at entry, 32 years; 11,221 mothers, 9841 fathers). Bereaved parents who had lost a child of the same sex had similar overall mortality as bereaved parents who had lost a child of the opposite sex (HR = 1.02; 95% CI, 0.85–1.22). Similar findings were observed for mortality due to natural death (HR = 0.96; 95% CI, 0.78–1.18) or mortality due to unnatural death (HR = 1.22; 95% CI, 0.84–1.77). Bereaved fathers who had lost a son had similar mortality as those bereaved by the death of a daughter (HR = 1.10; 95% CI, 0.86–1.40). Bereaved mothers who had lost a daughter had similar mortality as those bereaved by the death of a son (HR = 0.93; 95% CI, 0.70–1.22). Bereaved parents who had lost a son had mortality rates similar to those who had lost a daughter (HR = 1.09; 95% CI, 0.91–1.31). The interactions between grouping variable and sex of parents were not significant, indicating that the differential effect of losing a child based on sex of the child was not greater for fathers than for mothers.Conclusions: The results of this study revealed no significant effect of sex of the deceased child on mortality in these bereaved parents. The results might differ if this study was replicated in a population with a different grief culture and, more importantly, different gender schemas. 相似文献
156.
Saskia L. Smits Anna de Lang Judith M. A. van den Brand Lonneke M. Leijten Wilfred F. van IJcken Marinus J. C. Eijkemans Geert van Amerongen Thijs Kuiken Arno C. Andeweg Albert D. M. E. Osterhaus Bart L. Haagmans 《PLoS pathogens》2010,6(2)
The emergence of viral respiratory pathogens with pandemic potential, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and influenza A H5N1, urges the need for deciphering their pathogenesis to develop new intervention strategies. SARS-CoV infection causes acute lung injury (ALI) that may develop into life-threatening acute respiratory distress syndrome (ARDS) with advanced age correlating positively with adverse disease outcome. The molecular pathways, however, that cause virus-induced ALI/ARDS in aged individuals are ill-defined. Here, we show that SARS-CoV-infected aged macaques develop more severe pathology than young adult animals, even though viral replication levels are similar. Comprehensive genomic analyses indicate that aged macaques have a stronger host response to virus infection than young adult macaques, with an increase in differential expression of genes associated with inflammation, with NF-κB as central player, whereas expression of type I interferon (IFN)-β is reduced. Therapeutic treatment of SARS-CoV-infected aged macaques with type I IFN reduces pathology and diminishes pro-inflammatory gene expression, including interleukin-8 (IL-8) levels, without affecting virus replication in the lungs. Thus, ALI in SARS-CoV-infected aged macaques developed as a result of an exacerbated innate host response. The anti-inflammatory action of type I IFN reveals a potential intervention strategy for virus-induced ALI. 相似文献
157.
158.
Saskia van Hemert Arjan J.W. Hoekman Mari A. Smits Johanna M.J. Rebel 《Comparative biochemistry and physiology. Part D, Genomics & proteomics》2006,1(3):292-299
So far the responses of chickens to Salmonella have not been studied in vivo on a whole genome-wide scale. Furthermore, the influence of the host genetic background on gene expression responses is unknown. In this study gene expression profiles in the chicken (Gallus gallus) intestine of two genetically different chicken lines were compared, 24 h after a Salmonella enteritidis inoculation in 1-day-old chicks. The two chicken lines differed in the severity of the systemic infection. For gene expression profiles, a whole genome oligonucleotide array and a cDNA microarray were used to compare both platforms. Genes upregulated in both chicken lines after the Salmonella infection had a function in the innate immune system or in wound healing. Genes regulated after the Salmonella infection in one chicken line encoded proteins involved in inflammation, or with unknown functions. In the other chicken line upregulated genes encoded proteins involved in acute phase response, the fibrinogen system, actin polymerisation, or with unknown functions. Some of the host gene responses found in this study are not described before as response to a bacterial infection in the intestine. The two chicken lines reacted with different intestinal gene responses to the Salmonella infection, implying that it is important to use chickens with different genetic background to study gene expression responses. 相似文献
159.
Colorectal cancer still represents one of the most common causes of morbidity and mortality among Western populations. The adenomatous polyposis coli (APC) gene, originally identified as the gene responsible for familial adenomatous polyposis (FAP), an inherited predisposition to multiple colorectal tumors, is now considered as the true "gatekeeper" of colonic epithelial proliferation. It is mutated in the vast majority of sporadic colorectal tumors, and inactivation of both APC alleles occurs at early stages of tumor development in man and mouse. The study of FAP has also led to one of the most consistent genotype-phenotype correlations in hereditary cancer. However, great phenotypic variability is still observed not only among carriers of the identical APC mutation from unrelated families but also from within the same kindred. The generation of several mouse models carrying specific Apc mutations on the same inbred genetic background has confirmed the genotype-phenotype correlations initially established among FAP patients, as well as provided important insights into the mechanisms of colorectal tumor formation. Here we review the major features of the available animal models for FAP and attempt the formulation of a hypothetical model for APC-driven tumorigenesis based on the observed genetic and phenotypic variability in mouse and man. 相似文献
160.
Creemers EE Davis JN Parkhurst AM Leenders P Dowdy KB Hapke E Hauet AM Escobar PG Cleutjens JP Smits JF Daemen MJ Zile MR Spinale FG 《American journal of physiology. Heart and circulatory physiology》2003,284(1):H364-H371
Recent studies have been directed at modulating the heart failure process through inhibition of activated matrix metalloproteinases (MMPs). We hypothesized that a loss of MMP inhibitory control by tissue inhibitor of MMP (TIMP)-1 deficiency alters the course of postinfarction chamber remodeling and induced chronic myocardial infarction (MI) in wild-type (WT) and TIMP-1(-/-) mice. Left ventricular (LV) pressure-volume loops obtained from WT and TIMP-1(-/-) mice demonstrated that LV end-diastolic volume [52 +/- 4 (WT) vs. 71 +/- 6 (TIMP-1(-/-)) microl] and LV end-diastolic pressure [9.0 +/- 1.2 (WT) vs. 12.7 +/- 1.4 (TIMP-1(-/-)) mmHg] were significantly increased in the TIMP-1(-/-) mice 2 wk after MI. LV contractility was reduced to a similar degree in the WT and TIMP-1(-/-) groups after MI, as indicated by a significant fall in the LV end-systolic pressure-volume relationship. Ventricular weight and cross-sectional areas of LV myocytes were significantly increased in TIMP-1(-/-) mice, indicating that the hypertrophic response was more pronounced. The observed significant loss of fibrillar collagen in the TIMP-1(-/-) controls may have been an important contributory factor for the observed LV alterations in the TIMP-1(-/-) mice after MI. These findings demonstrate that TIMP-1 deficiency amplifies adverse LV remodeling after MI in mice and emphasizes the importance of local endogenous control of cardiac MMP activity by TIMP-1. 相似文献