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61.
A single motif responsible for ubiquitin recognition and monoubiquitination in endocytic proteins 总被引:42,自引:0,他引:42
Polo S Sigismund S Faretta M Guidi M Capua MR Bossi G Chen H De Camilli P Di Fiore PP 《Nature》2002,416(6879):451-455
Ubiquitination is a post-translation modification in which ubiquitin chains or single ubiquitin molecules are appended to target proteins, giving rise to poly- or monoubiquitination, respectively. Polyubiquitination targets proteins for destruction by the proteasome. The role of monoubiquitination is less understood, although a function in membrane trafficking is emerging, at least in yeast. Here we report that a short amino-acid stretch at the carboxy-termini of the monoubiquitinated endocytic proteins Eps15 and eps15R is indispensable for their monoubiquitination. A similar sequence, also required for this modification, is found in other cytosolic endocytic proteins, such as epsins and Hrs. These sequences comprise a protein motif, UIM (ref. 6), which has been proposed to bind to ubiquitin. We confirm this for the UIMs of eps15, eps15R, epsins and Hrs. Thus, the same motif in several endocytic proteins is responsible for ubiquitin recognition and monoubiquitination. Our results predict the existence of a UIM:ubiquitin-based intracellular network. Eps15/eps15R, epsins and Hrs may function as adaptors between ubiquitinated membrane cargo and either the clathrin coat or other endocytic scaffolds. In addition, through their own ubiquitination, they may further contribute to the amplification of this network in the endocytic pathway. 相似文献
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McClelland M Sanderson KE Clifton SW Latreille P Porwollik S Sabo A Meyer R Bieri T Ozersky P McLellan M Harkins CR Wang C Nguyen C Berghoff A Elliott G Kohlberg S Strong C Du F Carter J Kremizki C Layman D Leonard S Sun H Fulton L Nash W Miner T Minx P Delehaunty K Fronick C Magrini V Nhan M Warren W Florea L Spieth J Wilson RK 《Nature genetics》2004,36(12):1268-1274
Salmonella enterica serovars often have a broad host range, and some cause both gastrointestinal and systemic disease. But the serovars Paratyphi A and Typhi are restricted to humans and cause only systemic disease. It has been estimated that Typhi arose in the last few thousand years. The sequence and microarray analysis of the Paratyphi A genome indicates that it is similar to the Typhi genome but suggests that it has a more recent evolutionary origin. Both genomes have independently accumulated many pseudogenes among their approximately 4,400 protein coding sequences: 173 in Paratyphi A and approximately 210 in Typhi. The recent convergence of these two similar genomes on a similar phenotype is subtly reflected in their genotypes: only 30 genes are degraded in both serovars. Nevertheless, these 30 genes include three known to be important in gastroenteritis, which does not occur in these serovars, and four for Salmonella-translocated effectors, which are normally secreted into host cells to subvert host functions. Loss of function also occurs by mutation in different genes in the same pathway (e.g., in chemotaxis and in the production of fimbriae). 相似文献
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Maser RS Choudhury B Campbell PJ Feng B Wong KK Protopopov A O'Neil J Gutierrez A Ivanova E Perna I Lin E Mani V Jiang S McNamara K Zaghlul S Edkins S Stevens C Brennan C Martin ES Wiedemeyer R Kabbarah O Nogueira C Histen G Aster J Mansour M Duke V Foroni L Fielding AK Goldstone AH Rowe JM Wang YA Look AT Stratton MR Chin L Futreal PA DePinho RA 《Nature》2007,447(7147):966-971
Highly rearranged and mutated cancer genomes present major challenges in the identification of pathogenetic events driving the neoplastic transformation process. Here we engineered lymphoma-prone mice with chromosomal instability to assess the usefulness of mouse models in cancer gene discovery and the extent of cross-species overlap in cancer-associated copy number aberrations. Along with targeted re-sequencing, our comparative oncogenomic studies identified FBXW7 and PTEN to be commonly deleted both in murine lymphomas and in human T-cell acute lymphoblastic leukaemia/lymphoma (T-ALL). The murine cancers acquire widespread recurrent amplifications and deletions targeting loci syntenic to those not only in human T-ALL but also in diverse human haematopoietic, mesenchymal and epithelial tumours. These results indicate that murine and human tumours experience common biological processes driven by orthologous genetic events in their malignant evolution. The highly concordant nature of genomic events encourages the use of genomically unstable murine cancer models in the discovery of biological driver events in the human oncogenome. 相似文献
64.
Greenman C Stephens P Smith R Dalgliesh GL Hunter C Bignell G Davies H Teague J Butler A Stevens C Edkins S O'Meara S Vastrik I Schmidt EE Avis T Barthorpe S Bhamra G Buck G Choudhury B Clements J Cole J Dicks E Forbes S Gray K Halliday K Harrison R Hills K Hinton J Jenkinson A Jones D Menzies A Mironenko T Perry J Raine K Richardson D Shepherd R Small A Tofts C Varian J Webb T West S Widaa S Yates A Cahill DP Louis DN Goldstraw P Nicholson AG Brasseur F Looijenga L Weber BL Chiew YE DeFazio A 《Nature》2007,446(7132):153-158
Cancers arise owing to mutations in a subset of genes that confer growth advantage. The availability of the human genome sequence led us to propose that systematic resequencing of cancer genomes for mutations would lead to the discovery of many additional cancer genes. Here we report more than 1,000 somatic mutations found in 274 megabases (Mb) of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers. There was substantial variation in the number and pattern of mutations in individual cancers reflecting different exposures, DNA repair defects and cellular origins. Most somatic mutations are likely to be 'passengers' that do not contribute to oncogenesis. However, there was evidence for 'driver' mutations contributing to the development of the cancers studied in approximately 120 genes. Systematic sequencing of cancer genomes therefore reveals the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated. 相似文献
65.
DNA sequence has long been recognized as an important contributor to nucleosome positioning, which has the potential to regulate access to genes. The extent to which the nucleosomal architecture at promoters is delineated by the underlying sequence is now being worked out. Here we use comparative genomics to report a genome-wide map of nucleosome positioning sequences (NPSs) located in the vicinity of all Saccharomyces cerevisiae genes. We find that the underlying DNA sequence provides a very good predictor of nucleosome locations that have been experimentally mapped to a small fraction of the genome. Notably, distinct classes of genes possess characteristic arrangements of NPSs that may be important for their regulation. In particular, genes that have a relatively compact NPS arrangement over the promoter region tend to have a TATA box buried in an NPS and tend to be highly regulated by chromatin modifying and remodeling factors. 相似文献
66.
Sara C. Zapico Sofía T. Menéndez Paula Núñez 《Cellular and molecular life sciences : CMLS》2014,71(15):2957-2962
Estimation of time since death is one of the challenges in forensic science. There are many approaches to estimate the postmortem interval, including both physical and thanatochemistry methods. Decomposition is triggered by a process called autolysis, which induces destructive changes in the cell leading to cell death. Based on the process of cell death signaling, this study analyzed the early postmortem interval (2–8 h since death) using the study of the mRNA expression of Fas Ligand (FasL) and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) by Quantitative-PCR. Results of the study indicate a time-dependent increase in the mRNA levels of both proteins up until 6 h after death. Using a regression analysis in these first 6 h, a positive linear correlation was found between the mRNA expression of these proteins and the time since death. Since PTEN and FasL are implicated in signaling pathways, both proteins are potential candidates to analyze the time since death in time intervals of 6 h or less. Further research is needed to find additional cell death markers and expand the time period for time since death estimation. 相似文献
67.
Tarpey PS Raymond FL Nguyen LS Rodriguez J Hackett A Vandeleur L Smith R Shoubridge C Edkins S Stevens C O'Meara S Tofts C Barthorpe S Buck G Cole J Halliday K Hills K Jones D Mironenko T Perry J Varian J West S Widaa S Teague J Dicks E Butler A Menzies A Richardson D Jenkinson A Shepherd R Raine K Moon J Luo Y Parnau J Bhat SS Gardner A Corbett M Brooks D Thomas P Parkinson-Lawrence E Porteous ME Warner JP Sanderson T Pearson P Simensen RJ Skinner C Hoganson G Superneau D Wooster R Bobrow M 《Nature genetics》2007,39(9):1127-1133
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Martin MP Qi Y Gao X Yamada E Martin JN Pereyra F Colombo S Brown EE Shupert WL Phair J Goedert JJ Buchbinder S Kirk GD Telenti A Connors M O'Brien SJ Walker BD Parham P Deeks SG McVicar DW Carrington M 《Nature genetics》2007,39(6):733-740
Allotypes of the natural killer (NK) cell receptor KIR3DL1 vary in both NK cell expression patterns and inhibitory capacity upon binding to their ligands, HLA-B Bw4 molecules, present on target cells. Using a sample size of over 1,500 human immunodeficiency virus (HIV)+ individuals, we show that various distinct allelic combinations of the KIR3DL1 and HLA-B loci significantly and strongly influence both AIDS progression and plasma HIV RNA abundance in a consistent manner. These genetic data correlate very well with previously defined functional differences that distinguish KIR3DL1 allotypes. The various epistatic effects observed here for common, distinct KIR3DL1 and HLA-B Bw4 combinations are unprecedented with regard to any pair of genetic loci in human disease, and indicate that NK cells may have a critical role in the natural history of HIV infection. 相似文献
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