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Telomere dysfunction in aging and cancer 总被引:5,自引:0,他引:5
Gilley D Tanaka H Herbert BS 《The international journal of biochemistry & cell biology》2005,37(5):1000-1013
Telomeres are unique DNA-protein structures that contain noncoding TTAGGG repeats and telomere-associated proteins. These specialized structures are essential for maintaining genomic integrity. Alterations that lead to the disruption of telomere maintenance result in chromosome end-to-end fusions and/or ends being recognized as double-strand breaks. A large body of evidence suggests that the cell responds to dysfunctional telomeres by undergoing senescence, apoptosis, or genomic instability. In conjunction with other predisposing mechanisms, the genomic instability encountered in preimmortal cells due to dysfunctional or uncapped telomeres might lead to cancer. Furthermore, telomere dysfunction has been proposed to play critical roles in aging as well as cancer progression. Conversely, recent evidence has shown that targeting telomere maintenance mechanisms and inducing telomere dysfunction in cancer cells by inhibiting telomerase can lead to catastrophic events including rapid cell death and increased sensitivity to other cancer therapeutics. Thus, given the major role telomeres play during development, it is important to continue our understanding telomere structure, function and maintenance. Herein, we provide an overview of the emerging knowledge of telomere dysfunction and how it relates to possible links between aging and cancer. 相似文献
74.
Background
Irreversible airflow obstruction in Chronic Obstructive Pulmonary Disease (COPD) is thought to result from airway remodelling associated with aberrant inflammation. Patients who experience frequent episodes of acute deterioration in symptoms and lung function, termed exacerbations, experience a faster decline in their lung function, and thus over time greater disease severity However the mechanisms by which these episodes may contribute to decreased lung function are poorly understood.This study has prospectively examined changes in sputum levels of inflammatory cells, MMP-9 and TIMP-1 during exacerbations comparing with paired samples taken prior to exacerbation.Methods
Nineteen COPD patients ((median, [IQR]) age 69 [63 to 74], forced expiratory volume in one second (FEV1) 1.0 [0.9 to1.2], FEV1% predicted 37.6 [27.3 to 46.2]) provided sputa at exacerbation. Of these, 12 were paired with a samples collected when the patient was stable, a median 4 months [2 to 8 months] beforehand.Results
MMP-9 levels increased from 10.5 μg/g [1.2 to 21.1] prior to exacerbation to 17.1 μg/g [9.3 to 48.7] during exacerbation (P < 0.01). TIMP-1 levels decreased from 3.5 μg/g [0.6 to 7.8] to 1.5 μg/g [0.3 to 4.9] (P = 0.16). MMP-9/TIMP-1 Molar ratio significantly increased from 0.6 [0.2 to 1.1] to 3.6 [2.0 to 25.3] (P < 0.05). Neutrophil, eosinophil and lymphocyte counts all showed significant increase during exacerbation compared to before (P < 0.05). Macrophage numbers remained level. MMP-9 levels during exacerbation showed highly significant correlation with both neutrophil and lymphocyte counts (Rho = 0.7, P < 0.01).Conclusion
During exacerbation, increased inflammatory burden coincides with an imbalance of the proteinase MMP-9 and its cognate inhibitor TIMP-1. This may suggest a pathway connecting frequent exacerbations with lung function decline. 相似文献75.
S.?S.?SchneiderEmail author T.?Deeby D.?C.?Gilley G.?DeGrandi-Hoffman 《Insectes Sociaux》2004,51(4):359-364
Summary. Nest usurpation is a form of reproductive parasitism that may contribute to the ability of African bees to displace European honey bees in the Americas. We examined nest usurpation by African swarms over a two-year period in a southern-Arizona apiary that contained 76 five-frame European colonies. We observed a mean annual usurpation rate of 21% , with strong seasonal trends in usurpation activity. Most usurpations occurred from October–December, with a minor peak of usurpation activity in the spring-summer months. The seasonal patterns of usurpation corresponded with the reproductive swarming season in spring and summer and the absconding season in the fall-winter months. Queenless colonies, colonies that contained a queen confined in a cage, and those that had been recently requeened were 2–8 times more likely to be invaded than were colonies that contained an actively laying queen, suggesting that queen condition may have a major influence on host-colony susceptibility to usurpation. This trend was particularly pronounced in October–December, during which months the usurpation rates experienced by caged-queen and queenless colonies approached 20–50%. Our results show that nest usurpation is seasonally frequent among honey bees in the southwestern U.S., which suggests that reproductive parasitism contributes to the invasion success of African honey bees and possibly other introduced social insect species.Received 3 February 2004; revised 8 April 2004; accepted 17 April 2004. 相似文献
76.
In order to reconstruct phylogenetic trees from extremely dissimilar
sequences it is necessary to estimate accurately the extent of sequence
divergence. In this paper a new method of sequence analysis, Markov triple
analysis, is developed for determining the relative frequencies of
nucleotide substitutions within the three branches of a three-taxon
dendrogram. Assuming that nucleotide sites are independently and
identically distributed and assuming a Markov model for nucleotide (or
protein) evolution, it is shown that the unique Markov matrices can be
reconstructed given only the joint probability distribution relating three
taxa. (In the much simpler case involving only two taxa and two character
states, Markov matrices can also be reconstructed, provided symmetry
assumptions are placed on the elements of the matrices.) The method is
illustrated using sequence data from the combined first and second codon
positions derived from complete human, mouse, and cow mitochondrial
sequences.
相似文献
77.
DNA hybridization evidence for the principal lineages of hummingbirds (Aves:Trochilidae) 总被引:3,自引:0,他引:3
The spectacular evolutionary radiation of hummingbirds (Trochilidae) has
served as a model system for many biological studies. To begin to provide a
historical context for these investigations, we generated a complete matrix
of DNA hybridization distances among 26 hummingbirds and an outgroup swift
(Chaetura pelagica) to determine the principal hummingbird lineages. FITCH
topologies estimated from symmetrized delta TmH-C values and subjected to
various validation methods (bootstrapping, weighted jackknifing, branch
length significance) indicated a fundamental split between hermit
(Eutoxeres aquila, Threnetes ruckeri; Phaethornithinae) and nonhermit
(Trochilinae) hummingbirds, and provided strong support for six principal
nonhermit clades with the following branching order: (1) a predominantly
lowland group comprising caribs (Eulampis holosericeus) and relatives
(Androdon aequatorialis and Heliothryx barroti) with violet-ears (Colibri
coruscans) and relatives (Doryfera ludovicae); (2) an Andean-associated
clade of highly polytypic taxa (Eriocnemis, Heliodoxa, and Coeligena); (3)
a second endemic Andean clade (Oreotrochilus chimborazo, Aglaiocercus
coelestis, and Lesbia victoriae) paired with thorntails (Popelairia
conversii); (4) emeralds and relatives (Chlorostilbon mellisugus, Amazilia
tzacatl, Thalurania colombica, Orthorhyncus cristatus and Campylopterus
villaviscensio); (5) mountain-gems (Lampornis clemenciae and Eugenes
fulgens); and (6) tiny bee-like forms (Archilochus colubris, Myrtis fanny,
Acestrura mulsant, and Philodice mitchellii). Corresponding analyses on a
matrix of unsymmetrized delta values gave similar support for these
relationships except that the branching order of the two Andean clades (2,
3 above) was unresolved. In general, subsidiary relationships were
consistent and well supported by both matrices, sometimes revealing
surprising associations between forms that differ dramatically in plumage
and bill morphology. Our results also reveal some basic aspects of
hummingbird ecologic and morphologic evolution. For example, most of the
diverse endemic Andean assemblage apparently comprises two genetically
divergent clades, whereas the majority of North American hummingbirds
belong a single third clade. Genetic distances separating some
morphologically distinct genera (Oreotrochilus, Aglaiocercus, Lesbia;
Myrtis, Acestrura, Philodice) were no greater than among congeneric
(Coeligena) species, indicating that, in hummingbirds, morphological
divergence does not necessarily reflect level of genetic divergence.
相似文献
78.
79.
Pamela A. Lochhead Jonathan Clark Lan-Zhen Wang Lesley Gilmour Matthew Squires Rebecca Gilley 《Cell cycle (Georgetown, Tex.)》2016,15(4):506-518
ERK5, encoded by MAPK7, has been proposed to play a role in cell proliferation, thus attracting interest as a cancer therapeutic target. While oncogenic RAS or BRAF cause sustained activation of the MEK1/2-ERK1/2 pathway, ERK5 is directly activated by MEK5. It has been proposed that RAS and RAF proteins can also promote ERK5 activation. Here we investigated the interplay between RAS-RAF-MEK-ERK and ERK5 signaling and studied the role of ERK5 in tumor cell proliferation in 2 disease-relevant cell models. We demonstrate that although an inducible form of CRAF (CRAF:ER*) can activate ERK5 in fibroblasts, the response is delayed and reflects feed-forward signaling. Additionally, oncogenic KRAS and BRAF do not activate ERK5 in epithelial cells. Although KRAS and BRAF do not couple directly to MEK5-ERK5, ERK5 signaling might still be permissive for proliferation. However, neither the selective MEK5 inhibitor BIX02189 or ERK5 siRNA inhibited proliferation of colorectal cancer cells harbouring KRASG12C/G13D or BRAFV600E. Furthermore, there was no additive or synergistic effect observed when BIX02189 was combined with the MEK1/2 inhibitor Selumetinib (AZD6244), suggesting that ERK5 was neither required for proliferation nor a driver of innate resistance to MEK1/2 inhibitors. Finally, even cancer cells with MAPK7 amplification were resistant to BIX02189 and ERK5 siRNA, showing that ERK5 amplification does not confer addiction to ERK5 for cell proliferation. Thus ERK5 signaling is unlikely to play a role in tumor cell proliferation downstream of KRAS or BRAF or in tumor cells with ERK5 amplification. These results have important implications for the role of ERK5 as an anti-cancer drug target. 相似文献
80.