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91.
Akt, an essential component of the insulin pathway, is a potent inducer of tissue growth. One of Akt''s phosphorylation targets is Tsc2, an inhibitor of the anabolic kinase TOR. This could account for part of Akt''s growth promoting activity. Although phosphorylation of Tsc2 by Akt does occur in vivo, and under certain circumstances can lead to reduced Tsc2 activity, the functional significance of this event is unclear since flies lacking Akt phosphorylation sites on Tsc2 are viable and normal in size and growth rate. Since Drosophila Tsc1, the obligate partner of Tsc2, has an Akt phosphorylation motif that is not conserved in mammals, we investigate here whether Akt redundantly phosphorylates the Tsc complex on Tsc1 and Tsc2. We provide evidence that Akt phosphorylates Tsc1 at Ser533. We show that flies lacking Akt phosphorylation sites on Tsc1 alone, or on both Tsc1 and Tsc2 concurrently, are viable and normal in size. This shows that phosphorylation of the Tsc1/2 complex by Akt is not required for Akt to activate TORC1 and to promote tissue growth in Drosophila. 相似文献
92.
Neasham D Gallo V Guarrera S Dunning A Overvad K Tjonneland A Clavel-Chapelon F Linseisen JP Malaveille C Ferrari P Boeing H Benetou V Trichopoulou A Palli D Crosignani P Tumino R Panico S Bueno-De-Mesquita HB Peeters PH van Gib CH Lund E Gonzalez CA Martinez C Dorronsoro M Barricarte A Navarro C Quiros JR Berglund G Jarvholm B Khaw KT Key TJ Bingham S Diaz TM Riboli E Matullo G Vineis P 《DNA Repair》2009,8(1):60-71
We followed-up for mortality and cancer incidence 1088 healthy non-smokers from a population-based study, who were characterized for 22 variants in 16 genes involved in DNA repair pathways. Follow-up was 100% complete. The association between polymorphism and mortality or cancer incidence was analyzed using Cox Proportional Hazard regression models. Ninety-five subjects had died in a median follow-up time of 78 months (inter-quartile range 59-93 months). None of the genotypes was clearly associated with total mortality, except variants for two Double-Strand Break DNA repair genes, XRCC3 18067 C>T (rs#861539) and XRCC2 31479 G>A (rs#3218536). Adjusted hazard ratios were 2.25 (1.32-3.83) for the XRCC3 C/T genotype and 2.04 (1.00-4.13) for the T/T genotype (reference C/C), and 2.12 (1.14-3.97) for the XRCC2 G/A genotype (reference G/G). For total cancer mortality, the adjusted hazard ratios were 3.29 (1.23-7.82) for XRCC3 C/T, 2.84 (0.81-9.90) for XRCC3 T/T and 3.17 (1.21-8.30) for XRCC2 G/A. With combinations of three or more adverse alleles, the adjusted hazard ratio for all cause mortality was 17.29 (95% C.I. 8.13-36.74), and for all incident cancers the HR was 5.28 (95% C.I. 2.17-12.85). Observations from this prospective study suggest that polymorphisms of genes involved in the repair of DNA double-strand breaks significantly influence the risk of cancer and non-cancer disease, and can influence mortality. 相似文献
93.
Caroline Mauvezin Meritxell Orpinell Víctor A Francis Francisco Mansilla Jordi Duran Vicent Ribas Manuel Palacín Patricia Boya Aurelio A Teleman Antonio Zorzano 《EMBO reports》2010,11(1):37-44
The regulation of autophagy in metazoans is only partly understood, and there is a need to identify the proteins that control this process. The diabetes‐ and obesity‐regulated gene (DOR), a recently reported nuclear cofactor of thyroid hormone receptors, is expressed abundantly in metabolically active tissues such as muscle. Here, we show that DOR shuttles between the nucleus and the cytoplasm, depending on cellular stress conditions, and re‐localizes to autophagosomes on autophagy activation. We demonstrate that DOR interacts physically with autophagic proteins Golgi‐associated ATPase enhancer of 16 kDa (GATE16) and microtubule‐associated protein 1A/1B‐light chain 3. Gain‐of‐function and loss‐of‐function studies indicate that DOR stimulates autophagosome formation and accelerates the degradation of stable proteins. CG11347, the DOR Drosophila homologue, has been predicted to interact with the Drosophila Atg8 homologues, which suggests functional conservation in autophagy. Flies lacking CG11347 show reduced autophagy in the fat body during pupal development. All together, our data indicate that DOR regulates autophagosome formation and protein degradation in mammalian and Drosophila cells. 相似文献
94.
Boto A Gallardo JA Hernández R Ledo F Muñoz A Murguía JR Menacho-Márquez M Orjales A Saavedra CJ 《Bioorganic & medicinal chemistry letters》2006,16(23):6073-6077
The discovery of genotoxic amino acids derived from phenylglycine, and possessing halogen substituents, is described. The utility of hypervalent iodine reagents in the synthesis of this class of compounds is highlighted. The mechanism of action of the (haloaryl)glycines was studied in Saccharomyces cerevisiae. 相似文献
95.
Aurelio A. de los Reyes V Eunok Jung Franz Kappel 《Bulletin of mathematical biology》2014,76(6):1306-1332
In this paper, we develop a pulsatile model for the cardiovascular system which describes the reaction of this system to a submaximal constant workload imposed on a person at a bicycle ergometer test after a period of rest. Furthermore, the model should allow to use measurements for the pulsatile pressure in fingertips which provide information on the diastolic and the systolic pressure for parameter estimation. Based on the assumption that the baroreceptor loop is the essential control loop in this case, we design a stabilizing feedback control for the pulsatile model which is obtained by solving a linear-quadratic regulator problem for the linearization of a non-pulsatile counterpart of the pulsatile model. We also investigate the behavior of the model with respect to changes in the weight of the term in the cost functional for the linear-quadratic regulator problem which penalizes the deviation of the momentary pressure in the aorta from the pressure at the stationary situation which should be obtained. 相似文献
96.
97.
Teleman AA 《Cell》2011,146(3):346-347
When developing animals encounter nutrient restriction, most tissues stop growing. Some vital tissues, however, such as the brain, continue to grow. Now, Cheng et?al. (2011) identify Alk as the kinase that allows the Drosophila brain to continue growing during nutrient restriction by bypassing the requirements for insulin receptor and TOR activation. 相似文献
98.
99.
Francesca Langone Stefano Cannata Claudia Fuoco Daniele Lettieri Barbato Stefano Testa Aurelio Pio Nardozza Maria Rosa Ciriolo Luisa Castagnoli Cesare Gargioli Gianni Cesareni 《PloS one》2014,9(12)
The skeletal muscle tissue has a remarkable capacity to regenerate upon injury. Recent studies have suggested that this regenerative process is improved when AMPK is activated. In the muscle of young and old mice a low calorie diet, which activates AMPK, markedly enhances muscle regeneration. Remarkably, intraperitoneal injection of AICAR, an AMPK agonist, improves the structural integrity of muscles of dystrophin-deficient mdx mice. Building on these observations we asked whether metformin, a powerful anti-hyperglycemic drug, which indirectly activates AMPK, affects the response of skeletal muscle to damage. In our conditions, metformin treatment did not significantly influence muscle regeneration. On the other hand we observed that the muscles of metformin treated mice are more resilient to cardiotoxin injury displaying lesser muscle damage. Accordingly myotubes, originated in vitro from differentiated C2C12 myoblast cell line, become more resistant to cardiotoxin damage after pre-incubation with metformin. Our results indicate that metformin limits cardiotoxin damage by protecting myotubes from necrosis. Although the details of the molecular mechanisms underlying the protective effect remain to be elucidated, we report a correlation between the ability of metformin to promote resistance to damage and its capacity to counteract the increment of intracellular calcium levels induced by cardiotoxin treatment. Since increased cytoplasmic calcium concentrations characterize additional muscle pathological conditions, including dystrophies, metformin treatment could prove a valuable strategy to ameliorate the conditions of patients affected by dystrophies. 相似文献
100.
The mitochondrial genome (mtDNA), due to its peculiar features such as exclusive presence of orthologous genes, uniparental inheritance, lack of recombination, small size and constant gene content, certainly represents a major model system in studies on evolutionary genomics in metazoan. In 800 million years of evolution the gene content of metazoan mitochondrial genomes has remained practically frozen but several evolutionary processes have taken place. These processes, reviewed here, include rearrangements of gene order, changes in base composition and arising of compositional asymmetry between the two strands, variations in the genetic code and evolution of codon usage, lineage-specific nucleotide substitution rates and evolutionary patterns of mtDNA control regions. 相似文献