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81.
82.
Phylogenetic screening of the human genome: identification of differentially hybridizing repetitive sequence families 总被引:1,自引:0,他引:1
The phi-screen, a method of phylogenetic screening, can be employed to
detect repetitive sequence families that differentially hybridize between
closely related species. Such differences may involve sequence divergence
or variations in copy number, including total presence versus absence of a
family of repeated DNA. We present the results of a phi-screen comparing
the human genome to that of the prosimian, Galago crassicaudatus. Three
human repetitive families that are divergent or not present in galago have
been detected. One of these families is described in detail; it is similar
among the anthropoids but is present in a lower copy number and/or
divergent form in prosimians. The family is clearly related to the
transposon-like human element (THE) described by Paulson et al. (1985).
THEs have long terminal repeats reminiscent of retroviruses but are unique
in that they have no sequence similarity to known mammalian retroviruses.
The sequence of a solo long terminal repeat, found unassociated with THE
internal sequence, is presented. This family member, THE p2, is bordered by
a 5-bp target-site repeat and is interrupted by the insertion of an Alu
element. A solo THE element sequenced by Wiginton et al. (1986) contains an
insertion of Alu at precisely the same position as does THE p2.
相似文献
83.
84.
Trapani F Del Basso De Caro ML Insabato L Papparella S Paciello O 《Folia histochemica et cytobiologica / Polish Academy of Sciences, Polish Histochemical and Cytochemical Society》2010,48(3):403-406
The Silent Corticotroph Adenoma (SCA) is a pituitary adenoma variant characterized by the immunoreactivity for adrenocorticotropic hormone (ACTH) and related peptides, without the clinical signs of Cushing's disease. SCA has been postulated to either secrete structurally abnormal ACTH that is inactive but detectable by immunohistochemistry or radioimmunoassay, or to secrete ACTH intermittently or at low levels continuously. Excess of ACTH has been associated to type II muscle atrophy. We describe a case of type II muscle fibers atrophy associated with silent corticotroph adenoma in a dog. The dog showed moderate to severe proximal muscle wasting and weakness with normal levels of muscle-associated enzymes. In the limb muscle biopsies, type II fibers were uniformly smaller than type I fibers. In temporalis muscles, there were few atrophic fibers, and several irregular areas of loss of enzymatic activity observed in NADH, SDH and COX stains. The tumour showed a trabecular growth pattern and immunohistochemical analysis demonstrated the presence of cytoplasmic immunoreactivity for ACTH. The muscle atrophy was considered to be related to an excess of inactive ACTH. Studying spontaneous occurring rare diseases in animals could help to understand the mechanism of similar diseases in human has well. 相似文献
85.
Natalya Lukoyanova Stephanie C. Kondos Irene Farabella Ruby H. P. Law Cyril F. Reboul Tom T. Caradoc-Davies Bradley A. Spicer Oded Kleifeld Daouda A. K. Traore Susan M. Ekkel Ilia Voskoboinik Joseph A. Trapani Tamas Hatfaludi Katherine Oliver Eileen M. Hotze Rodney K. Tweten James C. Whisstock Maya Topf Helen R. Saibil Michelle A. Dunstone 《PLoS biology》2015,13(2)
Membrane attack complex/perforin-like (MACPF) proteins comprise the largest superfamily of pore-forming proteins, playing crucial roles in immunity and pathogenesis. Soluble monomers assemble into large transmembrane pores via conformational transitions that remain to be structurally and mechanistically characterised. Here we present an 11 Å resolution cryo-electron microscopy (cryo-EM) structure of the two-part, fungal toxin Pleurotolysin (Ply), together with crystal structures of both components (the lipid binding PlyA protein and the pore-forming MACPF component PlyB). These data reveal a 13-fold pore 80 Å in diameter and 100 Å in height, with each subunit comprised of a PlyB molecule atop a membrane bound dimer of PlyA. The resolution of the EM map, together with biophysical and computational experiments, allowed confident assignment of subdomains in a MACPF pore assembly. The major conformational changes in PlyB are a ∼70° opening of the bent and distorted central β-sheet of the MACPF domain, accompanied by extrusion and refolding of two α-helical regions into transmembrane β-hairpins (TMH1 and TMH2). We determined the structures of three different disulphide bond-trapped prepore intermediates. Analysis of these data by molecular modelling and flexible fitting allows us to generate a potential trajectory of β-sheet unbending. The results suggest that MACPF conformational change is triggered through disruption of the interface between a conserved helix-turn-helix motif and the top of TMH2. Following their release we propose that the transmembrane regions assemble into β-hairpins via top down zippering of backbone hydrogen bonds to form the membrane-inserted β-barrel. The intermediate structures of the MACPF domain during refolding into the β-barrel pore establish a structural paradigm for the transition from soluble monomer to pore, which may be conserved across the whole superfamily. The TMH2 region is critical for the release of both TMH clusters, suggesting why this region is targeted by endogenous inhibitors of MACPF function. 相似文献
86.
Cutting edge: granzymes A and B are not essential for perforin-mediated tumor rejection 总被引:6,自引:0,他引:6
Controversy still exists regarding the biological function of granzyme serine proteases released with perforin from the cytotoxic granules of NK cells and CTLs. In particular, it is not clear whether the major granzymes, A and B, play an essential role in tumor rejection mediated by the perforin pathway. We have now examined the relative importance of perforin and granzyme A and B clusters in five different tumor models that stringently distinguish their importance. We conclude that granzyme A and B clusters are not essential for CTL- and NK cell-mediated rejection of spontaneous and experimental tumors, raising the likelihood that either perforin alone or in combination with an additional granzyme or granule component(s) mediates cytotoxicity of tumor cells in vivo. 相似文献
87.
88.
Perforin-dependent nuclear entry of granzyme B precedes apoptosis, and is not a consequence of nuclear membrane dysfunction 总被引:5,自引:0,他引:5
Trapani JA Jans P Smyth MJ Froelich CJ Williams EA Sutton VR Jans DA 《Cell death and differentiation》1998,5(6):488-496
Killer lymphocytes utilize the synergy of a membranolytic protein, perforin, and the serine protease granzyme B (grB) to induce target cell apoptosis, however the mechanism of this synergy remains incompletely defined. We have previously shown that perforin specifically induces the redistribution of cytoplasmic grB into the nucleus of dying cells, however a causal role for nuclear targeting of grB in cell death has not been demonstrated. In the present study, we used confocal laser scanning microscopy (CLSM) to determine whether the nuclear accumulation of fluoresceinated (FITC-) grB precedes or is a consequence of apoptosis. Two distinct and mutually exclusive cellular responses were observed in FDC-P1 cells: (i) up to 50% of the cells rapidly accumulated FITC-grB in the nucleus (maximal at 7 min; t1/2 of 2 min) and underwent apoptosis; (ii) the remaining cells took up FITC-grB only into the cytoplasm, and escaped apoptosis. Under these conditions, DNA fragmentation was not observed for at least 13 min, indicating nuclear accumulation of grB preceded the execution phase of apoptosis. Furthermore, nuclear import of grB proceeded through an intact nuclear membrane, as the nuclei of cells whose cytoplasm was pre-loaded with 70 kDa FITC-dextran excluded dextran for up to 90 min while still undergoing apoptosis in response to perforin and grB. These findings indicated that perforin-induced nuclear accumulation of grB precedes apoptosis, and is not a by-product of caspase-induced nuclear membrane degradation. The cell membrane lesions formed by perforin in these experiments were not large enough to permit a 13 kDa protein (yeast cdk p13suc) access into the cytoplasm, but an 8 kDa protein (bacterial azurin) was able to equilibrate between the cytosol and the exterior. Therefore, transmembrane pores large enough to allow passive diffusion of grB (32 kDa) into the cell are not necessary for apoptosis. Rather, a perforin-dependent signal results in a redistribution of grB from the cytoplasm to the nucleus, where it may contribute to the nuclear changes associated with apoptosis. 相似文献
89.
Perforin-dependent nuclear targeting of granzymes: A central role in the nuclear events of granule-exocytosis-mediated apoptosis? 总被引:4,自引:0,他引:4
Programmed cell death, apoptosis, involves very distinctive changes within the target cell nucleus, including margination of the chromatin, DNA fragmentation and breakdown of the nuclear envelope. Cytolytic granule-mediated target cell apoptosis is effected, in part, through synergistic action of the membrane-acting protein perforin and serine proteases, such as granzymes A or B. Recent work using confocal laser scanning microscopy as well as other techniques supports the idea that perforin-dependent translocation of granzymes to the nucleus of target cells plays a central role in effecting the nuclear changes associated with apoptosis. In vitro experiments indicate that granzyme nuclear import follows a novel pathway, being independent of ATP, not inhibitable by non-hydrolysable GTP analogues and involving binding within the nucleus, unlike conventional signal- dependent nuclear protein import. In intact cells, perforin-dependent nuclear entry of granzymes precedes the nuclear events of apoptosis such as DNA fragmentation and nuclear envelope breakdown; prevention of granzyme nuclear translocation through bcl2 overexpression or treatment of target cells with inhibitors of caspase activation blocks these events. Nuclear localization of granzymes thus appears to be central to induction of the nuclear changes associated with cytolytic granule-mediated apoptosis. 相似文献
90.
Cresswell KS Clarke CJ Jackson JT Darcy PK Trapani JA Johnstone RW 《Biochemical and biophysical research communications》2005,326(2):417-424
The human HIN-200 family member AIM2 was originally identified in a screen for suppressors of melanoma tumorigenicity following introduction of chromosome 6 into the UACC903 human melanoma cell line. Although the AIM2 protein contained many of the conserved structural motifs common to other HIN-200 proteins, the biochemical characteristics of AIM2 and the ability of overexpressed AIM2 to phenocopy the effect of introduction of chromosome 6 in the UACC903 cells had not been assessed. Herein we demonstrated that AIM2 was localised within the nucleus of transfected or interferon-treated human cells. In addition, AIM2 could homodimerise via the amino-terminal (PAAD/DAPIN) region and heterodimerise with the related IFI 16 protein. However, overexpressed AIM2 did not significantly affect the growth or survival of UACC903 cells or another human melanoma cell line. These data indicate that AIM2 has many of the biochemical and structural characteristics of HIN-200 proteins, however, its expression is not sufficient to induce a tumor-suppressor-like phenotype. 相似文献