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排序方式: 共有81条查询结果,搜索用时 15 毫秒
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Inactivation of the apoptosis effector Apaf-1 in malignant melanoma 总被引:47,自引:0,他引:47
Soengas MS Capodieci P Polsky D Mora J Esteller M Opitz-Araya X McCombie R Herman JG Gerald WL Lazebnik YA Cordón-Cardó C Lowe SW 《Nature》2001,409(6817):207-211
Metastatic melanoma is a deadly cancer that fails to respond to conventional chemotherapy and is poorly understood at the molecular level. p53 mutations often occur in aggressive and chemoresistant cancers but are rarely observed in melanoma. Here we show that metastatic melanomas often lose Apaf-1, a cell-death effector that acts with cytochrome c and caspase-9 to mediate p53-dependent apoptosis. Loss of Apaf-1 expression is accompanied by allelic loss in metastatic melanomas, but can be recovered in melanoma cell lines by treatment with the methylation inhibitor 5-aza-2'-deoxycytidine (5aza2dC). Apaf-1-negative melanomas are invariably chemoresistant and are unable to execute a typical apoptotic programme in response to p53 activation. Restoring physiological levels of Apaf-1 through gene transfer or 5aza2dC treatment markedly enhances chemosensitivity and rescues the apoptotic defects associated with Apaf-1 loss. We conclude that Apaf-1 is inactivated in metastatic melanomas, which leads to defects in the execution of apoptotic cell death. Apaf-1 loss may contribute to the low frequency of p53 mutations observed in this highly chemoresistant tumour type. 相似文献
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Aggressive behavior is pervasive throughout the animal kingdom, and yet very little is known about its molecular underpinnings. To address this problem, we have developed a population-based selection procedure to increase aggression in Drosophila melanogaster. We measured changes in aggressive behavior in the selected subpopulations with a new two-male arena assay. In only ten generations of selection, the aggressive lines became markedly more aggressive than the neutral lines. After 21 generations, the fighting index increased more than 30-fold. Using microarray analysis, we identified genes with differing expression levels in the aggressive and neutral lines as candidates for this strong behavioral selection response. We tested a small set of these genes through mutant analysis and found that one significantly increased fighting frequency. These results suggest that selection for increases in aggression can be used to molecularly dissect this behavior. 相似文献
4.
Residues of the variable region of the T-cell-receptor beta-chain that interact with S. aureus toxin superantigens 总被引:29,自引:0,他引:29
The alpha beta T-cell antigen receptor (TCR) recognizes antigenic peptides in the context of self major histocompatibility complex (MHC) molecules. The specificity of recognition of MHC plus antigen is generally determined by a combination of the variable elements of alpha- and beta-chains of the TCR. Several types of antigen, however, have been identified that, when bound to MHC molecules, stimulate T cells bearing particular variable-region beta-chain (V beta) elements irrespective of the other variable components of the TCR. These have been termed 'superantigens', and here we are concerned with one type of superantigen, the toxins produced by Staphylococcus aureus. T cells have been found that bear closely related members of the same V beta family but respond differently to S. aureus toxins; in particular, cells bearing the human V beta 13.2 element respond to toxin SEC2, whereas cells bearing human V beta 13.1 do not. We have now defined the residues of the V beta element responsible for this difference, and find that they reside in a region thought to lie on the side of the TCR molecule, away from the conventional antigen/MHC-binding site. The evolutionary conservation of this site may be due to its having an important role in some function of the TCR other than the binding of conventional antigen plus MHC. 相似文献
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Systematic screen for human disease genes in yeast 总被引:19,自引:0,他引:19
Steinmetz LM Scharfe C Deutschbauer AM Mokranjac D Herman ZS Jones T Chu AM Giaever G Prokisch H Oefner PJ Davis RW 《Nature genetics》2002,31(4):400-404
High similarity between yeast and human mitochondria allows functional genomic study of Saccharomyces cerevisiae to be used to identify human genes involved in disease. So far, 102 heritable disorders have been attributed to defects in a quarter of the known nuclear-encoded mitochondrial proteins in humans. Many mitochondrial diseases remain unexplained, however, in part because only 40-60% of the presumed 700-1,000 proteins involved in mitochondrial function and biogenesis have been identified. Here we apply a systematic functional screen using the pre-existing whole-genome pool of yeast deletion mutants to identify mitochondrial proteins. Three million measurements of strain fitness identified 466 genes whose deletions impaired mitochondrial respiration, of which 265 were new. Our approach gave higher selection than other systematic approaches, including fivefold greater selection than gene expression analysis. To apply these advantages to human disorders involving mitochondria, human orthologs were identified and linked to heritable diseases using genomic map positions. 相似文献
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CpG methylation is maintained in human cancer cells lacking DNMT1 总被引:31,自引:0,他引:31
Rhee I Jair KW Yen RW Lengauer C Herman JG Kinzler KW Vogelstein B Baylin SB Schuebel KE 《Nature》2000,404(6781):1003-1007
Hypermethylation is associated with the silencing of tumour susceptibility genes in several forms of cancer; however, the mechanisms responsible for this aberrant methylation are poorly understood. The prototypic DNA methyltransferase, DNMT1, has been widely assumed to be responsible for most of the methylation of the human genome, including the abnormal methylation found in cancers. To test this hypothesis, we disrupted the DNMT1 gene through homologous recombination in human colorectal carcinoma cells. Here we show that cells lacking DNMT1 exhibited markedly decreased cellular DNA methyltransferase activity, but there was only a 20% decrease in overall genomic methylation. Although juxtacentromeric satellites became significantly demethylated, most of the loci that we analysed, including the tumour suppressor gene p16INK4a, remained fully methylated and silenced. These results indicate that DNMT1 has an unsuspected degree of regional specificity in human cells and that methylating activities other than DNMT1 can maintain the methylation of most of the genome. 相似文献
10.
J M Derry E Gormally G D Means W Zhao A Meindl R I Kelley Y Boyd G E Herman 《Nature genetics》1999,22(3):286-290
Tattered (Td) is an X-linked, semi-dominant mouse mutation associated with prenatal male lethality. Heterozygous females are small and at 4-5 days of age develop patches of hyperkeratotic skin where no hair grows, resulting in a striping of the coat in adults. Craniofacial anomalies and twisted toes have also been observed in some affected females. A potential second allele of Td has also been described. The phenotype of Td is similar to that seen in heterozygous females with human X-linked dominant chondrodysplasia punctata (CDPX2, alternatively known as X-linked dominant Conradi-Hünermann-Happle syndrome) as well as another X-linked, semi-dominant mouse mutation, bare patches (Bpa). The Bpa gene has recently been identified and encodes a protein with homology to 3beta-hydroxysteroid dehydrogenases that functions in one of the later steps of cholesterol biosynthesis. CDPX2 patients display skin defects including linear or whorled atrophic and pigmentary lesions, striated hyperkeratosis, coarse lusterless hair and alopecia, cataracts and skeletal abnormalities including short stature, rhizomelic shortening of the limbs, epiphyseal stippling and craniofacial defects (MIM 302960). We have now identified the defect in Td mice as a single amino acid substitution in the delta8-delta7 sterol isomerase emopamil binding protein (Ebp; encoded by Ebp in mouse) and identified alterations in human EBP in seven unrelated CDPX2 patients. 相似文献