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191.
Securin degradation is mediated by fzy and fzr, and is required for complete chromatid separation but not for cytokinesis 总被引:19,自引:0,他引:19
We have studied the ubiquitination and degradation patterns of the human securin/PTTG protein. We show that, in contrast to budding yeast pds1, securin degradation is catalyzed by both fzy (fizzy/cdc20) and fzr (fizzy-related/cdh1/hct1). Both fzy and fzr also induce the APC/C to ubiquitinate securin in vitro. Securin degradation is mediated by an RXXL destruction box and a KEN box, and is inhibited only when both sequences are mutated. Interestingly, the non-degradable securin mutant is also partially ubiquitinated by fzy and fzr in vitro. Expressing the non-degradable securin mutant in cells frequently resulted in incomplete chromatid separation and gave rise to daughter cells connected by a thin chromatin fiber, presumably of chromosomes that failed to split completely. Strikingly, the mutant securin did not prevent the majority of sister chromatids from separating completely, nor did it prevent mitotic cyclin degradation and cytokinesis. This phenotype, reminiscent of the fission yeast cut (cells untimely torn) phenotype, is reported here for the first time in mammals. 相似文献
192.
Increased incidence of squamous cell carcinomas in Mastomys natalensis papillomavirus E6 transgenic mice during two-stage skin carcinogenesis 总被引:2,自引:0,他引:2
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Helfrich I Chen M Schmidt R Fürstenberger G Kopp-Schneider A Trick D Gröne HJ Zur Hausen H Rösl F 《Journal of virology》2004,78(9):4797-4805
Papillomaviruses cause certain forms of human cancers, most notably carcinomas of the uterine cervix. In contrast to the well-established involvement of papillomavirus infection in the etiology of cervical carcinomas and in carcinomas of a rare hereditary condition, epidermodysplasia verruciformis, a causative role for cutaneous human papillomavirus types in the development of nonmelanoma skin cancer has not been proven. In order to better understand the functions of individual genes of cutaneous papillomavirus types, we generated transgenic mice carrying oncogene E6 of the Mastomys natalensis papillomavirus (MnPV), which causes keratoacanthomas of the skin in its natural host. In the present study, we demonstrate that under conditions of experimental two-stage skin carcinogenesis, fast-paced squamous cell carcinomas develop in nearly 100% of MnPV E6 transgenic mice in comparison to 10% in their nontransgenic littermates (log rank test; P < 0.0001). Therefore, we conclude that the MnPV E6 transgene favors the malignant progression of chemically induced tumors. Whereas an activating H-ras mutation is a consistent feature in benign and malignant tumors in wild-type mice, the majority of papillomas and keratoacanthomas and all squamous cell carcinomas obtained in MnPV E6 transgenic mice contain nonmutated ras alleles. These results indicate that the development of squamous cell carcinomas in MnPV E6 transgenic mice does not depend on an activated H-ras oncogene. 相似文献
193.
The estimation of the number of protein folds in nature is a matter of considerable interest. In this study, a Monte Carlo method employing the broken stick model is used to assign a given number of proteins into a given number of folds. Subsequently, random, integer, non-repeating numbers are generated in order to simulate the process of fold discovery. With this conceptual framework at hand, the effects of two factors upon the fold identification process were investigated: (1) the nature of folds distributions and (2) preferential sampling bias of previously identified folds. Depending on the type of distribution, dividing 100,000 proteins into 1,000 folds resulted in 10-30% of the folds having 10 proteins or less per fold, approximately 10% of the folds having 10-20 proteins per fold, 31-45% having 20-100 proteins per fold, and >30% of the folds having more than 100 proteins per fold. After randomly sampling one tenth of the proteins, 68-96% of the folds were identified. These percentages depend both on folds distribution and biased/non-biased sampling. Only upon increasing the sampling bias for previously identified folds to 1,000, did the model result in a reduction of the number of proteins identified by an order of magnitude (approximately 9%). Thus, assuming the structures of one tenth of the population of proteins in nature have been solved, the results of the Monte Carlo simulation are more consistent with recent lower estimates of the number of folds, 相似文献
194.
Modeling the structure of the respiratory syncytial virus small hydrophobic protein by silent-mutation analysis of global searching molecular dynamics
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Kochva U Leonov H Arkin IT 《Protein science : a publication of the Protein Society》2003,12(12):2668-2674
Human respiratory syncytial virus (RSV) encodes a small hydrophobic (SH) protein, whose function in the life cycle of the virus is unknown. Recent channel activity measurements of the protein suggest that like other viroporins, SH may assemble into a homo-oligomeric ion channel. To further our understanding of this potentially important protein, a new strategy was implemented in order to model the transmembrane oligomeric bundle of the protein. Global searching molecular dynamic simulations of SH proteins from eight different viral strains, each at different oligomeric states, as well as different lengths of the putative transmembrane domain, were undertaken. Taken together, a total of 45 different global molecular dynamic simulations pointed to a single pentameric structure for the protein that was found in all of the different variants. The model of the structure obtained is a channel-like homopentamer whose minimal transmembrane pore diameter is 1.46 A. 相似文献
195.
196.
Transmembrane helices and the helical bundles which they form are the major building blocks of membrane proteins. Since helices are characterized by a given periodicity, it is possible to search for patterns of traits which typify one side of the helix and not the other (e.g. amphipathic helices contain a polar and apolar sides). Using Fourier transformation we have analyzed solved membrane protein structures as well as sequences of membrane proteins from the Swiss-Prot database. The traits searched included aromaticity, volume and ionization. While a number of motifs were already recognized in the literature, many were not. One particular example involved helix VII of lactose permease which contains seven aromatic residues on six helical turns. Similarly six glycine residues in four consecutive helical turns were identified as forming a motif in the chloride channel. A tabulation of all the findings is presented as well as a possible rationalization of the function of the motif. 相似文献
197.
Clemens S Bloss T Vess C Neumann D Nies DH Zur Nieden U 《The Journal of biological chemistry》2002,277(20):18215-18221
The cation diffusion facilitator (CDF) family represents a class of ubiquitous metal transporters. Inactivation of a CDF in Schizosaccharomyces pombe, Zhf, causes drastically different effects on the tolerance toward various metals. A deletion mutant is Zn(2+)/Co(2+)-hypersensitive yet displays significantly enhanced Cd(2+) and Ni(2+) tolerance. Accumulation of zinc, cobalt, and cadmium is reduced in mutant cells. Non-vacuolar zinc content, as measured by analytical electron microscopy, is lower in zhf(-) cells compared with wild-type cells in the presence of elevated Zn(2+) concentrations. The protective effect against cadmium toxicity is independent of the phytochelatin detoxification pathway. Phytochelatin synthase-deficient cells show extremely enhanced (about 200-fold) cadmium tolerance when zhf is disrupted. Immunogold labeling indicates endoplasmic reticulum (ER) localization of Zhf. Electron spectroscopic imaging shows that accumulation of zinc coincides with Zhf localization, demonstrating a major role of the ER for metal storage and the involvement of Zhf in cellular zinc homeostasis. Also, these observations indicate that Cd(2+) ions exert their toxic effects on cellular metabolism in the ER rather than in the cytosol. 相似文献
198.
Ethanol exposure affects gene expression in the embryonic organizer and reduces retinoic acid levels
Yelin R Schyr RB Kot H Zins S Frumkin A Pillemer G Fainsod A 《Developmental biology》2005,279(1):193-204
Fetal Alcohol Spectrum Disorder (FASD) is a set of developmental malformations caused by alcohol consumption during pregnancy. Fetal Alcohol Syndrome (FAS), the strongest manifestation of FASD, results in short stature, microcephally and facial dysmorphogenesis including microphthalmia. Using Xenopus embryos as a model developmental system, we show that ethanol exposure recapitulates many aspects of FAS, including a shortened rostro-caudal axis, microcephally and microphthalmia. Temporal analysis revealed that Xenopus embryos are most sensitive to ethanol exposure between late blastula and early/mid gastrula stages. This window of sensitivity overlaps with the formation and early function of the embryonic organizer, Spemann's organizer. Molecular analysis revealed that ethanol exposure of embryos induces changes in the domains and levels of organizer-specific gene expression, identifying Spemann's organizer as an early target of ethanol. Ethanol also induces a defect in convergent extension movements that delays gastrulation movements and may affect the overall length. We show that mechanistically, ethanol is antagonistic to retinol (Vitamin A) and retinal conversion to retinoic acid, and that the organizer is active in retinoic acid signaling during early gastrulation. The model suggests that FASD is induced in part by an ethanol-dependent reduction in retinoic acid levels that are necessary for the normal function of Spemann's organizer. 相似文献
199.
Full-breadth analysis of CD8+ T-cell responses in acute hepatitis C virus infection and early therapy
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Lauer GM Lucas M Timm J Ouchi K Kim AY Day CL Schulze Zur Wiesch J Paranhos-Baccala G Sheridan I Casson DR Reiser M Gandhi RT Li B Allen TM Chung RT Klenerman P Walker BD 《Journal of virology》2005,79(20):12979-12988
Multispecific CD8(+) T-cell responses are thought to be important for the control of acute hepatitis C virus (HCV) infection, but to date little information is actually available on the breadth of responses at early time points. Additionally, the influence of early therapy on these responses and their relationships to outcome are controversial. To investigate this issue, we performed comprehensive analysis of the breadth and frequencies of virus-specific CD8(+) T-cell responses on the single epitope level in eight acutely infected individuals who were all started on early therapy. During the acute phase, responses against up to five peptides were identified. During therapy, CD8(+) T-cell responses decreased rather than increased as virus was controlled, and no new specificities emerged. A sustained virological response following completion of treatment was independent of CD8(+) T-cell responses, as well as CD4(+) T-cell responses. Rapid recrudescence also occurred despite broad CD8(+) T-cell responses. Importantly, in vivo suppression of CD3(+) T cells using OKT3 in one subject did not result in recurrence of viremia. These data suggest that broad CD8(+) T-cell responses alone may be insufficient to contain HCV replication, and also that early therapy is effective independent of such responses. 相似文献
200.
Hadas Reuveni Shoshana Klein Alexander Levitzki 《European journal of biochemistry》2003,270(13):2759-2772
HR12 is a novel farnesyltransferase inhibitor (FTI). We have shown previously that HR12 induces phenotypic reversion of H-rasV12-transformed Rat1 (Rat1/ras) fibroblasts. This reversion was characterized by formation of cell-cell contacts, focal adhesions and stress fibers. Here we show that HR12 inhibits anchorage independent and dependent growth of Rat1/ras cells. HR12 also suppresses motility and proliferation of Rat1/ras cells, in a wound healing assay. Rat1 fibroblasts transformed with myristoylated H-rasV12 (Rat1/myr-ras) were resistant to HR12. Thus, the effects of HR12 are due to the inhibition of farnesylation of Ras. Cell growth of Rat1/ras cells was arrested at the G1 phase of the cell cycle. Analysis of cell cycle components showed that HR12 treatment of Rat1/ras cells led to elevated cellular levels of the cyclin-dependent kinase inhibitor p27Kip1 and inhibition of the kinase activity of the cyclin E/Cdk2 complex. This is the first time an FTI has been shown to lead to a rise in p27Kip1 levels in ras-transformed cells. The data suggest a new mechanism for FTI action, whereby in ras-transformed cells, the FTI causes an increase in p27Kip1 levels, which in turn inhibit cyclin E/Cdk2 activity, leading to G1 arrest. 相似文献