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61.
Mice with targeted mutation of peroxiredoxin 6 develop normally but are susceptible to oxidative stress 总被引:10,自引:0,他引:10
Wang X Phelan SA Forsman-Semb K Taylor EF Petros C Brown A Lerner CP Paigen B 《The Journal of biological chemistry》2003,278(27):25179-25190
Reactive oxygen species, especially hydrogen peroxide, are important in cellular signal transduction. However, excessive amounts of these species damage tissues and cells by oxidizing virtually all important biomolecules. Peroxiredoxin 6 (PRDX6) (also called antioxidant protein 2, or AOP2) is a novel peroxiredoxin family member whose function in vivo is unknown. Through immunohistochemistry, we have determined that the PRDX6 protein was widely expressed in every tissue examined, most abundantly in epithelial cells. It was found in cytosol, but not in membranes, organelles, and nuclei fractions. Prdx6 mRNA was also expressed in every tissue examined. The widespread expression of Prdx6 suggested that its functions were quite important. To determine these functions, we generated Prdx6-targeted mutant (Prdx6-/-) mice, confirmed the gene disruption by Southern blots, PCR, RT-PCR, Western blots, and immunohistochemistry, and compared the effects of paraquat, hydrogen peroxide, and t-butyl hydroperoxide on Prdx6-/- and wild-type (Prdx6+/+) macrophages, and of paraquat on Prdx6-/- and Prdx6+/+ mice. Prdx6-/- macrophages had higher hydrogen peroxide levels, and lower survival rates; Prdx6-/- mice had significantly lower survival rates, more severe tissue damage, and higher protein oxidation levels. Additionally, there were no differences in the mRNA expression levels of other peroxiredoxins, glutathione peroxidases, catalase, superoxide dismutases, thioredoxins, and glutaredoxins between normal Prdx6-/- and Prdx6+/+ mice and those injected with paraquat. Our study provides in vivo evidence that PRDX6 is a unique non-redundant antioxidant that functions independently of other peroxiredoxins and antioxidant proteins. 相似文献
62.
In gram-negative organisms, high-affinity transport of iron substrates requires energy transduction to specific outer membrane receptors by the TonB-ExbB-ExbD complex. Vibrio cholerae encodes two TonB proteins, one of which, TonB1, recognizes only a subset of V. cholerae TonB-dependent receptors and does not facilitate transport through Escherichia coli receptors. To investigate the receptor specificity exhibited by V. cholerae TonB1, chimeras were created between V. cholerae TonB1 and E. coli TonB. The activities of the chimeric TonB proteins in iron utilization assays demonstrated that the C-terminal one-third of either TonB confers the receptor specificities associated with the full-length TonB. Single-amino-acid substitutions near the C terminus of V. cholerae TonB1 were identified that allowed TonB1 to recognize E. coli receptors and at least one V. cholerae TonB2-dependent receptor. This indicates that the very C-terminal end of V. cholerae TonB1 determines receptor specificity. The regions of the TonB-dependent receptors involved in specificity for a particular TonB protein were investigated in experiments involving domain switching between V. cholerae and E. coli receptors exhibiting different TonB specificities. Switching the conserved TonB box heptapeptides at the N termini of these receptors did not alter their TonB specificities. However, replacing the amino acid immediately preceding the TonB box in E. coli receptors with an aromatic residue allowed these receptors to use V. cholerae TonB1. Further, site-directed mutagenesis of the TonB box -1 residue in a V. cholerae TonB2-dependent receptor demonstrated that a large hydrophobic amino acid in this position promotes recognition of V. cholerae TonB1. These data suggest that the TonB box -1 position controls productive interactions with V. cholerae TonB1. 相似文献
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Yuan ZQ Feldman RI Sun M Olashaw NE Coppola D Sussman GE Shelley SA Nicosia SV Cheng JQ 《The Journal of biological chemistry》2002,277(33):29973-29982
Previous studies have demonstrated that AKT1 and AKT3 are activated by heat shock and oxidative stress via both phosphatidylinositol 3-kinase-dependent and -independent pathways. However, the activation and role of AKT2 in the stress response have not been fully elucidated. In this study, we show that AKT2 in epithelial cells is activated by UV-C irradiation, heat shock, and hyperosmolarity as well as by tumor necrosis factor alpha (TNFalpha) through a phosphatidylinositol 3-kinase-dependent pathway. The activation of AKT2 inhibits UV- and TNF alpha-induced c-Jun N-terminal kinase (JNK) and p38 activities that have been shown to be required for stress- and TNF alpha-induced programmed cell death. Moreover, AKT2 interacts with and phosphorylates I kappa B kinase alpha. The phosphorylation of I kappa B kinase alpha and activation of NF kappa B mediates AKT2 inhibition of JNK but not p38. Furthermore, phosphatidylinositol 3-kinase inhibitor or dominant negative AKT2 significantly enhances UV- and TNF alpha-induced apoptosis, whereas expression of constitutively active AKT2 inhibits programmed cell death in response to UV and TNFalpha -induced apoptosis by inhibition of stress kinases and provide the first evidence that AKT inhibits stress kinase JNK through activation of the NF kappa B pathway. 相似文献
65.
The SfiI endonuclease is a tetrameric protein with two DNA-binding clefts. It has to bind two copies of its recognition sequence, one at each cleft, before it cleaves DNA. While SfiI binds cooperatively to two cognate sites, it binds only one non-cognate DNA molecule at a time and the resultant complex is precluded from binding cognate DNA at the vacant cleft. To examine the communications between separate binding sites in a protein that synapses two segments of DNA, SfiI was tested with oligonucleotide duplexes containing its recognition sequence but with either R(p) or S(p) phosphorothioate linkages at the scissile bonds. Though SfiI has low activity on the R(p) and none against the S(p) diastereoisomer, it bound these duplexes in the same cooperative manner as oxyester duplexes, though with a reduced affinity for the S(p) derivative. It also formed complexes with one phosphorothioate-duplex and one oxyester-duplex but, when Mg(2+) was added to the hybrid complexes, the phosphorothioate moiety at one DNA-binding cleft prevented the enzyme from cleaving the oxyester duplex at the other cleft. SfiI is thus restrained from catalytic action until it recognises the correct nucleotide sequence at two DNA loci and the correct phosphodiester functions at both loci. 相似文献
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The prevalence and intensity of the hematophagous pennellid copepod Haemobaphes diceraus were monitored over a 10-mo period in shiner perch Cymatogaster aggregata at Pipers Lagoon, Nanaimo, British Columbia. The prevalence and mean intensity of metamorphosed adult female H. diceraus (n = 421) were 10.0% and 1.2 (+/-0.5 SD), respectively. The majority (97.9%) of infected fish had single infections, reflecting the possibility of intensity-dependent parasite-induced mortality, rejection of additional parasites, or both. Transforming females were detected throughout the year; however, there was no detectable seasonal pattern of colonization. Neither copepodids nor adult males of H. diceraus were observed on the gills of shiner perch, and this was consistent with the hypothesis that an intermediate host harbors these stages. Males of Haemobaphes sp. infected the gills of bay pipefish Syngnathus griseolineatus with a prevalence and mean intensity of 56.0% and 6.8 +/- 3.7, respectively. Transmission of H. diceraus to shiner perch probably occurs in inshore protected areas, where shiner perch ecologically overlap with the probable intermediate host of H. diceraus, the bay pipefish. 相似文献
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Fliih, a gelsolin-related cytoskeletal regulator essential for early mammalian embryonic development 下载免费PDF全文
Campbell HD Fountain S McLennan IS Berven LA Crouch MF Davy DA Hooper JA Waterford K Chen KS Lupski JR Ledermann B Young IG Matthaei KI 《Molecular and cellular biology》2002,22(10):3518-3526
The Drosophila melanogaster flightless I gene is required for normal cellularization of the syncytial blastoderm. Highly conserved homologues of flightless I are present in Caenorhabditis elegans, mouse, and human. We have disrupted the mouse homologue Fliih by homologous recombination in embryonic stem cells. Heterozygous Fliih mutant mice develop normally, although the level of Fliih protein is reduced. Cultured homozygous Fliih mutant blastocysts hatch, attach, and form an outgrowing trophoblast cell layer, but egg cylinder formation fails and the embryos degenerate. Similarly, Fliih mutant embryos initiate implantation in vivo but then rapidly degenerate. We have constructed a transgenic mouse carrying the complete human FLII gene and shown that the FLII transgene is capable of rescuing the embryonic lethality of the homozygous targeted Fliih mutation. These results confirm the specific inactivation of the Fliih gene and establish that the human FLII gene and its gene product are functional in the mouse. The Fliih mouse mutant phenotype is much more severe than in the case of the related gelsolin family members gelsolin, villin, and CapG, where the homozygous mutant mice are viable and fertile but display alterations in cytoskeletal actin regulation. 相似文献