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271.
Mullen AR Wheaton WW Jin ES Chen PH Sullivan LB Cheng T Yang Y Linehan WM Chandel NS DeBerardinis RJ 《Nature》2012,481(7381):385-388
Mitochondrial metabolism provides precursors to build macromolecules in growing cancer cells. In normally functioning tumour cell mitochondria, oxidative metabolism of glucose- and glutamine-derived carbon produces citrate and acetyl-coenzyme A for lipid synthesis, which is required for tumorigenesis. Yet some tumours harbour mutations in the citric acid cycle (CAC) or electron transport chain (ETC) that disable normal oxidative mitochondrial function, and it is unknown how cells from such tumours generate precursors for macromolecular synthesis. Here we show that tumour cells with defective mitochondria use glutamine-dependent reductive carboxylation rather than oxidative metabolism as the major pathway of citrate formation. This pathway uses mitochondrial and cytosolic isoforms of NADP(+)/NADPH-dependent isocitrate dehydrogenase, and subsequent metabolism of glutamine-derived citrate provides both the acetyl-coenzyme A for lipid synthesis and the four-carbon intermediates needed to produce the remaining CAC metabolites and related macromolecular precursors. This reductive, glutamine-dependent pathway is the dominant mode of metabolism in rapidly growing malignant cells containing mutations in complex I or complex III of the ETC, in patient-derived renal carcinoma cells with mutations in fumarate hydratase, and in cells with normal mitochondria subjected to acute pharmacological ETC inhibition. Our findings reveal the novel induction of a versatile glutamine-dependent pathway that reverses many of the reactions of the canonical CAC, supports tumour cell growth, and explains how cells generate pools of CAC intermediates in the face of impaired mitochondrial metabolism. 相似文献
272.
Ellis MJ Ding L Shen D Luo J Suman VJ Wallis JW Van Tine BA Hoog J Goiffon RJ Goldstein TC Ng S Lin L Crowder R Snider J Ballman K Weber J Chen K Koboldt DC Kandoth C Schierding WS McMichael JF Miller CA Lu C Harris CC McLellan MD Wendl MC DeSchryver K Allred DC Esserman L Unzeitig G Margenthaler J Babiera GV Marcom PK Guenther JM Leitch M Hunt K Olson J Tao Y Maher CA Fulton LL Fulton RS Harrison M Oberkfell B Du F Demeter R Vickery TL Elhammali A Piwnica-Worms H McDonald S Watson M Dooling DJ 《Nature》2012,486(7403):353-360
To correlate the variable clinical features of oestrogen-receptor-positive breast cancer with somatic alterations, we studied pretreatment tumour biopsies accrued from patients in two studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to haematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology and low proliferation rates, whereas mutant TP53 was associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in oestrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumour biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing. 相似文献
273.
274.
Cities lead the way in climate-change action 总被引:2,自引:0,他引:2
275.
276.
This paper presents a network equilibrium formulation for modeling commuters' travel choices in a bimodal transport system with park-and-ride (P&R) trips while the total demand is elastic to the congestion level of the network. A super-network approach is adopted in the proposed model. It is assumed that commuters' trips are categorized into two types, auto mode only and a combined mode with both auto and transit modes. The former is referred to as the pure mode trip and the latter as the P&R mode trip. The proposed model simultaneously considers the commuter's choice of the pure mode versus the P&R mode, the choice of parking location for the pure mode, the choice of transfer point for the P&R mode, as well as the route choice for each mode. The demand elasticity of transport system, the capacity constraints of transport facilities, and the congestion interaction throughout the super-network are also explicitly incorporated into the proposed model. The results of the numerical experiment show the following key findings: (i) traditional parking/P&R models may overestimate or underestimate travel demand distribution over network; (ii) parking/P&R, transit scheduling, and carpooling schemes bring significant impacts on commuters' travel behavior and network performance; and (iii) different transport policies may be to some extent mutually substituted . 相似文献
277.
Maintenance of ploidy in sexually reproducing organisms requires a specialized form of cell division called meiosis that generates genetically diverse haploid gametes from diploid germ cells. Meiotic cells halve their ploidy by undergoing two rounds of nuclear division (meiosis I and II) after a single round of DNA replication. Research in Saccharomyces cerevisiae (budding yeast) has shown that four major deviations from the mitotic cell cycle during meiosis are essential for halving ploidy. The deviations are (1) formation of a link between homologous chromosomes by crossover, (2) monopolar attachment of sister kinetochores during meiosis I, (3) protection of centromeric cohesion during meiosis I, and (4) suppression of DNA replication following exit from meiosis I. In this review we present the current understanding of the above four processes in budding yeast and examine the possible conservation of molecular mechanisms from yeast to humans. 相似文献
278.
279.
Bass AJ Lawrence MS Brace LE Ramos AH Drier Y Cibulskis K Sougnez C Voet D Saksena G Sivachenko A Jing R Parkin M Pugh T Verhaak RG Stransky N Boutin AT Barretina J Solit DB Vakiani E Shao W Mishina Y Warmuth M Jimenez J Chiang DY Signoretti S Kaelin WG Spardy N Hahn WC Hoshida Y Ogino S Depinho RA Chin L Garraway LA Fuchs CS Baselga J Tabernero J Gabriel S Lander ES Getz G Meyerson M 《Nature genetics》2011,43(10):964-968
Prior studies have identified recurrent oncogenic mutations in colorectal adenocarcinoma and have surveyed exons of protein-coding genes for mutations in 11 affected individuals. Here we report whole-genome sequencing from nine individuals with colorectal cancer, including primary colorectal tumors and matched adjacent non-tumor tissues, at an average of 30.7× and 31.9× coverage, respectively. We identify an average of 75 somatic rearrangements per tumor, including complex networks of translocations between pairs of chromosomes. Eleven rearrangements encode predicted in-frame fusion proteins, including a fusion of VTI1A and TCF7L2 found in 3 out of 97 colorectal cancers. Although TCF7L2 encodes TCF4, which cooperates with β-catenin in colorectal carcinogenesis, the fusion lacks the TCF4 β-catenin-binding domain. We found a colorectal carcinoma cell line harboring the fusion gene to be dependent on VTI1A-TCF7L2 for anchorage-independent growth using RNA interference-mediated knockdown. This study shows previously unidentified levels of genomic rearrangements in colorectal carcinoma that can lead to essential gene fusions and other oncogenic events. 相似文献
280.
Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss 总被引:1,自引:0,他引:1
Klein CJ Botuyan MV Wu Y Ward CJ Nicholson GA Hammans S Hojo K Yamanishi H Karpf AR Wallace DC Simon M Lander C Boardman LA Cunningham JM Smith GE Litchy WJ Boes B Atkinson EJ Middha S B Dyck PJ Parisi JE Mer G Smith DI Dyck PJ 《Nature genetics》2011,43(6):595-600
DNA methyltransferase 1 (DNMT1) is crucial for maintenance of methylation, gene regulation and chromatin stability. DNA mismatch repair, cell cycle regulation in post-mitotic neurons and neurogenesis are influenced by DNA methylation. Here we show that mutations in DNMT1 cause both central and peripheral neurodegeneration in one form of hereditary sensory and autonomic neuropathy with dementia and hearing loss. Exome sequencing led to the identification of DNMT1 mutation c.1484A>G (p.Tyr495Cys) in two American kindreds and one Japanese kindred and a triple nucleotide change, c.1470-1472TCC>ATA (p.Asp490Glu-Pro491Tyr), in one European kindred. All mutations are within the targeting-sequence domain of DNMT1. These mutations cause premature degradation of mutant proteins, reduced methyltransferase activity and impaired heterochromatin binding during the G2 cell cycle phase leading to global hypomethylation and site-specific hypermethylation. Our study shows that DNMT1 mutations cause the aberrant methylation implicated in complex pathogenesis. The discovered DNMT1 mutations provide a new framework for the study of neurodegenerative diseases. 相似文献