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Deciphering genetic regulatory codes remains a challenge. Here, we present an effective approach to identifying in vivo condition-specific coregulation with cis-regulatory motifs and modules in the mouse genome. A resampling-based algorithm was adopted to cluster our microarray data of a stress response, which generated 35 tight clusters with unique expression patterns containing 811 genes of 5652 genes significantly altered. Database searches identified many known motifs within the 3-kb regulatory regions of 40 genes from 3 clusters and modules with six to nine motifs that were commonly shared by 60-100% of these genes. The upstream regulatory region contained the highest frequency of these common motifs. CisModule program predictions were comparable with the results from database searches and found four potentially novel motifs. This result indicates that these motifs and modules could be responsible for gene coregulation of the stress response in the lacrimal gland. 相似文献
114.
Laura C. Greaves Joanna L. Elson Marco Nooteboom John P. Grady Geoffrey A. Taylor Robert W. Taylor John C. Mathers Thomas B. L. Kirkwood Doug M. Turnbull 《PLoS genetics》2012,8(11)
Human ageing has been predicted to be caused by the accumulation of molecular damage in cells and tissues. Somatic mitochondrial DNA (mtDNA) mutations have been documented in a number of ageing tissues and have been shown to be associated with cellular mitochondrial dysfunction. It is unknown whether there are selective constraints, which have been shown to occur in the germline, on the occurrence and expansion of these mtDNA mutations within individual somatic cells. Here we compared the pattern and spectrum of mutations observed in ageing human colon to those observed in the general population (germline variants) and those associated with primary mtDNA disease. The pathogenicity of the protein encoding mutations was predicted using a computational programme, MutPred, and the scores obtained for the three groups compared. We show that the mutations associated with ageing are randomly distributed throughout the genome, are more frequently non-synonymous or frameshift mutations than the general population, and are significantly more pathogenic than population variants. Mutations associated with primary mtDNA disease were significantly more pathogenic than ageing or population mutations. These data provide little evidence for any selective constraints on the occurrence and expansion of mtDNA mutations in somatic cells of the human colon during human ageing in contrast to germline mutations seen in the general population. 相似文献
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116.
Bailey TJ El-Hodiri H Zhang L Shah R Mathers PH Jamrich M 《The International journal of developmental biology》2004,48(8-9):761-770
The paired-like homeobox-containing gene Rx has a critical role in the eye development of several vertebrate species including Xenopus, mouse, chicken, medaka, zebrafish and human. Rx is initially expressed in the anterior neural region of developing embryos, and later in the retina and ventral hypothalamus. Abnormal regulation or function of Rx results in severe abnormalities of eye formation. Overexpression of Rx in Xenopus and zebrafish embryos leads to overproliferation of retinal cells. A targeted elimination of Rx in mice results in a lack of eye formation. Mutations in Rx genes are the cause of the mouse mutation eyeless (ey1), the medaka temperature sensitive mutation eyeless (el) and the zebrafish mutation chokh. In humans, mutations in Rx lead to anophthalmia. All of these studies indicate that Rx genes are key factors in vertebrate eye formation. Because these results cannot be easily reconciled with the most popular dogmas of the field, we offer our interpretation of eye development and evolution. 相似文献
117.
Karlsson M Mathers J Dickinson RJ Mandl M Keyse SM 《The Journal of biological chemistry》2004,279(40):41882-41891
MAP kinase phosphatase (MKP)-3 is a cytoplasmic dual specificity protein phosphatase that specifically binds to and inactivates the ERK1/2 MAP kinases in mammalian cells. However, the molecular basis of the cytoplasmic localization of MKP-3 or its physiological significance is unknown. We have used MKP-3-green fluorescent protein fusions in conjunction with leptomycin B to show that the cytoplasmic localization of MKP-3 is mediated by a chromosome region maintenance-1 (CRM1)-dependent nuclear export pathway. Furthermore, the nuclear translocation of MKP-3 seen in the presence of leptomycin B is mediated by an active process, indicating that MKP-3 shuttles between the nucleus and cytoplasm. The amino-terminal noncatalytic domain of MKP-3 is both necessary and sufficient for nuclear export of the phosphatase and contains a single functional leucine-rich nuclear export signal (NES). Even though this domain of the protein also mediates the binding of MKP-3 to MAP kinase, we show that mutations of the kinase interaction motif which abrogate ERK2 binding do not affect MKP-3 localization. Conversely, mutation of the NES does not affect either the binding or phosphatase activity of MKP-3 toward ERK2, indicating that the kinase interaction motif and NES function independently. Finally, we demonstrate that the ability of MKP-3 to cause the cytoplasmic retention of ERK2 requires both a functional kinase interaction motif and NES. We conclude that in addition to its established function in the regulated dephosphorylation and inactivation of MAP kinase, MKP-3 may also play a role in determining the subcellular localization of its substrate. Our results reinforce the idea that regulatory proteins such as MKP-3 may play a key role in the spatio-temporal regulation of MAP kinase activity. 相似文献
118.
Control of Oxidative Sulfur Metabolism of Chlorobium limicola forma thiosulfatophilum 总被引:3,自引:0,他引:3
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A metered blend of anaerobic-grade N2, CO2, and H2S gases was introduced into an illuminated, 800-ml liquid volume, continuously stirred tank reactor. The system, described as an anaerobic gas-to-liquid phase fed-batch reactor, was used to investigate the effects of H2S flow rate and light energy on the accumulation of oxidized sulfur compounds formed by the photoautotroph Chlorobium limicola forma thiosulfatophilum during growth. Elemental sulfur was formed and accumulated in stoichiometric quantities when light energy and H2S molar flow rate levels were optimally adjusted in the presence of nonlimiting CO2. Deviation from the optimal H2S and light energy levels resulted in either oxidation of sulfur or complete inhibition of sulfide oxidation. Based on these observations, a model of sulfide and sulfur oxidases electrochemically coupled to the photosynthetic reaction center of Chlorobium spp. is presented. The dynamic deregulation of oxidative pathways may be a mechanism for supplying the photosynthetic reaction center with a continuous source of electrons during periods of varying light and substrate availability, as in pond ecosystems where Chlorobium spp. are found. Possible applications for a sulfide gas removal process are discussed. 相似文献
119.
Angstrom J; Teneberg S; Milh MA; Larsson T; Leonardsson I; Olsson BM; Halvarsson MO; Danielsson D; N aslund I; Ljungh A; Wadstrom T; Karlsson KA 《Glycobiology》1998,8(4):297-309
The possible role of glycosphingolipids as adhesion receptors for the human
gastric pathogen Helicobacter pylori was examined by use of radiolabeled
bacteria, or protein extracts from the bacterial cell surface, in the
thin-layer chromatogram binding assay. Of several binding specificities
found, the binding to lactosylceramide is described in detail here, the
others being reported elsewhere. By autoradiography a preferential binding
to lactosylceramide having sphingosine/phytosphingosine and 2-D hydroxy
fatty acids was detected, whereas lactosylceramide having sphingosine and
nonhydroxy fatty acids was consistently nonbinding. A selective binding of
H. pylori to lactosylceramide with phytosphingosine and 2-D hydroxy fatty
acid was obtained when the different lactosylceramide species were
incorporated into liposomes, but only in the presence of cholesterol,
suggesting that this selectivity may be present also in vivo . Importantly,
lactosylceramide with sphingosine and hydroxy fatty acids does not bind in
this assay. Furthermore, a lactosylceramide-based binding pattern obtained
for different trisaccharide glycosphingolipids is consistent with the
assumption that this selectivity is due to binding of a conformation of
lactosylceramide in which the oxygen of the 2-D fatty acid hydroxyl group
forms a hydrogen bond with the Glc hydroxy methyl group, yielding an
epitope presentation different from other possible conformers. An
alternative conformation that may come into consideration corresponds to
the crystal structure found for cerebroside, in which the fatty acid
hydroxyl group is free to interact directly with the adhesin. By isolating
glycosphingolipids from epithelial cells of human stomach from seven
individuals, a binding of H.pylori to the diglycosylceramide region of the
non-acid fraction could be demonstrated in one of these cases. Mass
spectrometry showed that the binding-active sample contained
diglycosylceramides with phytosphingosine and 2-D hydroxy fatty acids with
16-24 carbon atoms in agreement with the results related above.
相似文献
120.
E. M. Mathers D. F. Houlihan I. D. McCarthy L. J. Burren 《Journal of fish biology》1993,43(2):245-263
Groups of recently hatched fry of rainbow trout, Oncorhynchus mykiss were maintained in the laboratory in order to investigate the effects of age, ration level and temperature on whole body growth, nucleic acid concentrations, protein synthesis rates and enzyme activities. In fry of up to 30 days after hatching, which were feeding but still had some yolk sac, no significant change in mean RNA concentration was observed with ration level. In older fry of 50 days or more, when the yolk sac was completely absorbed and exogenous feeding fully established, the concentration of RNA was correlated with the rate of protein growth. RNA concentrations and activities of citrate synthase and lactate dehydrogenase were significantly different between fed and starved fry. As water temperature was raised (from 5 to 15° C), higher rates of protein growth were brought about by an increase in the rate of protein synthesis and also by increased efficiency of retention of synthesized protein (reduced protein turnover). In fed fry, no change in RNA concentration was found with increasing temperature, while the amount of RNA per cell (RNA: DNA) decreased, indicating that increased rates of protein synthesis were due to increased RNA efficiency. 相似文献