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1.
Horvath A Boikos S Giatzakis C Robinson-White A Groussin L Griffin KJ Stein E Levine E Delimpasi G Hsiao HP Keil M Heyerdahl S Matyakhina L Libè R Fratticci A Kirschner LS Cramer K Gaillard RC Bertagna X Carney JA Bertherat J Bossis I Stratakis CA 《Nature genetics》2006,38(7):794-800
Phosphodiesterases (PDEs) regulate cyclic nucleotide levels. Increased cyclic AMP (cAMP) signaling has been associated with PRKAR1A or GNAS mutations and leads to adrenocortical tumors and Cushing syndrome. We investigated the genetic source of Cushing syndrome in individuals with adrenocortical hyperplasia that was not caused by known defects. We performed genome-wide SNP genotyping, including the adrenocortical tumor DNA. The region with the highest probability to harbor a susceptibility gene by loss of heterozygosity (LOH) and other analyses was 2q31-2q35. We identified mutations disrupting the expression of the PDE11A isoform-4 gene (PDE11A) in three kindreds. Tumor tissues showed 2q31-2q35 LOH, decreased protein expression and high cyclic nucleotide levels and cAMP-responsive element binding protein (CREB) phosphorylation. PDE11A codes for a dual-specificity PDE that is expressed in adrenal cortex and is partially inhibited by tadalafil and other PDE inhibitors; its germline inactivation is associated with adrenocortical hyperplasia, suggesting another means by which dysregulation of cAMP signaling causes endocrine tumors. 相似文献
2.
SWAP-70 is a guanine-nucleotide-exchange factor that mediates signalling of membrane ruffling 总被引:9,自引:0,他引:9
Shinohara M Terada Y Iwamatsu A Shinohara A Mochizuki N Higuchi M Gotoh Y Ihara S Nagata S Itoh H Fukui Y Jessberger R 《Nature》2002,416(6882):759-763
Phosphoinositide-3-OH kinase (PI(3)K), activated through growth factor stimulation, generates a lipid second messenger, phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3). PtdIns(3,4,5)P3 is instrumental in signalling pathways that trigger cell activation, cytoskeletal rearrangement, survival and other reactions. However, some targets of PtdIns(3,4,5)P3 are yet to be discovered. We demonstrate that SWAP-70, a unique signalling protein, specifically binds PtdIns(3,4,5)P3. On stimulation by growth factors, cytoplasmic SWAP-70, which is dependent on PI(3)K but independent of Ras, moved to cell membrane rearrangements known as ruffles. However, mutant SWAP-70 lacking the ability to bind PtdIns(3,4,5)P3 blocked membrane ruffling induced by epidermal growth factor or platelet-derived growth factor. SWAP-70 shows low homology with Rac-guanine nucleotide exchange factors (GEFs), and catalyses PtdIns(3,4,5)P3-dependent guanine nucleotide exchange to Rac. SWAP-70-deficient fibroblasts showed impaired membrane ruffling after stimulation with epidermal growth factor, and failed to activate Rac fully. We conclude that SWAP-70 is a new type of Rac-GEF which, independently of Ras, transduces signals from tyrosine kinase receptors to Rac. 相似文献
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4.
Maria C. Shina Annette Müller-Taubenberger Can Ünal Michael Schleicher Michael Steinert Ludwig Eichinger Rolf Müller Rosemarie Blau-Wasser Gernot Glöckner Angelika A. Noegel 《Cellular and molecular life sciences : CMLS》2011,68(2):303-313
Dictyostelium discoideum harbors a short (CRN12) and a long coronin (CRN7) composed of one and two beta-propellers, respectively. They are primarily
present in the cell cortex and cells lacking CRN12 (corA
−) or CRN7 (corB
−) have defects in actin driven processes. We compared the characteristics of a mutant cell line (corA
−
/corB
−) lacking CRN12 and CRN7 with the single mutants focusing on cytokinesis, phagocytosis, chemotaxis and development. Cytokinesis,
uptake of small particles, and developmental defects were not enhanced in the corA
−
/corB
− strain as compared to the single mutants, whereas motility and phagocytosis of yeast particles were more severely impaired.
It appears that although both proteins affect the same processes they do not act in a redundant manner. Rather, they often
act antagonistically, which is in accordance with their proposed roles in the actin cytoskeleton where CRN12 acts in actin
disassembly whereas CRN7 stabilizes actin filaments and protects them from disassembly. 相似文献
5.
The massive star that underwent a collapse of its core to produce supernova (SN)1993J was subsequently identified as a non-variable red supergiant star in images of the galaxy M81 taken before explosion. It showed an excess in ultraviolet and B-band colours, suggesting either the presence of a hot, massive companion star or that it was embedded in an unresolved young stellar association. The spectra of SN1993J underwent a remarkable transformation from the signature of a hydrogen-rich type II supernova to one of a helium-rich (hydrogen-deficient) type Ib. The spectral and photometric peculiarities were best explained by models in which the 13-20 solar mass supergiant had lost almost its entire hydrogen envelope to a close binary companion, producing a 'type IIb' supernova, but the hypothetical massive companion stars for this class of supernovae have so far eluded discovery. Here we report photometric and spectroscopic observations of SN1993J ten years after the explosion. At the position of the fading supernova we detect the unambiguous signature of a massive star: the binary companion to the progenitor. 相似文献
6.
An efficient implementation of the topography adaptive filter based on local frequency estimation is proposed, where chirpz transform is applied to enhance the accuracy of the frequency estimation. As a byproduct of this adaptive filter, the linear approximated phase model of the interferogram is employed to improve the coherence estimation. The impacts of the adaptive filter on global and local phase unwrapping algorithms are discussed. Finally, aiming at the negative effect that the adaptive filter can bring to local phase unwrapping algorithms, a fusion scheme that takes advantage of least square and several local phase unwrapping algorithms is presented. 相似文献
7.
The mutational deterministic hypothesis for the origin and maintenance of sexual reproduction posits that sex enhances the ability of natural selection to purge deleterious mutations after recombination brings them together into single genomes. This explanation requires negative epistasis, a type of genetic interaction where mutations are more harmful in combination than expected from their separate effects. The conceptual appeal of the mutational deterministic hypothesis has been offset by our inability to identify the mechanistic and evolutionary bases of negative epistasis. Here we show that negative epistasis can evolve as a consequence of sexual reproduction itself. Using an artificial gene network model, we find that recombination between gene networks imposes selection for genetic robustness, and that negative epistasis evolves as a by-product of this selection. Our results suggest that sexual reproduction selects for conditions that favour its own maintenance, a case of evolution forging its own path. 相似文献
8.
Summary To produce antisera of high antibody concentration animals after sensitization with protein have been reinjected with lethal doses of the antigen, protected against the shock-effect by substances with antihistamin properties (as example Antistin). The antibody concentration was considerably higher in these animals as in the other non-protected group reinjected with the highest tolerated antigen dosage. 相似文献
9.
Kristina Y. Aguilera Rolf A. Brekken 《Cellular and molecular life sciences : CMLS》2014,71(2):299-309
Pericytes are critical for vascular morphogenesis and contribute to several pathologies, including cancer development and progression. The mechanisms governing pericyte migration and differentiation are complex and have not been fully established. Current literature suggests that platelet-derived growth factor/platelet-derived growth factor receptor-β, sphingosine 1-phosphate/endothelial differentiation gene-1, angiopoietin-1/tyrosine kinase with immunoglobulin-like and EGF-like domains 2, angiopoietin-2/tyrosine kinase with immunoglobulin-like and EGF-like domains 2, transforming growth factor β/activin receptor-like kinase 1, transforming growth factor β/activin receptor-like kinase 5, Semaphorin-3A/Neuropilin, and matrix metalloproteinase activity regulate the recruitment of pericytes to nascent vessels. Interestingly, many of these pathways are directly affected by secreted protein acidic and rich in cysteine (SPARC). Here, we summarize the function of these factors in pericyte migration and discuss if and how SPARC might influence these activities and thus provide an additional layer of control for the recruitment of vascular support cells. Additionally, the consequences of targeted inhibition of pericytes in tumors and the current understanding of pericyte recruitment in pathological environments are discussed. 相似文献
10.
Serotonin was determined in platelets of 47 patients with alcoholism during the state of withdrawal as well as in a group of healthy persons. The results show that serotonin values were significantly lower in the group of patients with alcoholism as compared with the control group of healthy persons. 相似文献