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1.
Attenuation of pattern recognition receptor signaling is mediated by a MAP kinase kinase kinase
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Sharon C Mithoe Christina Ludwig Michiel JC Pel Mara Cucinotta Alberto Casartelli Malick Mbengue Jan Sklenar Paul Derbyshire Silke Robatzek Corné MJ Pieterse Ruedi Aebersold Frank LH Menke 《EMBO reports》2016,17(3):441-454
Pattern recognition receptors (PRRs) play a key role in plant and animal innate immunity. PRR binding of their cognate ligand triggers a signaling network and activates an immune response. Activation of PRR signaling must be controlled prior to ligand binding to prevent spurious signaling and immune activation. Flagellin perception in Arabidopsis through FLAGELLIN‐SENSITIVE 2 (FLS2) induces the activation of mitogen‐activated protein kinases (MAPKs) and immunity. However, the precise molecular mechanism that connects activated FLS2 to downstream MAPK cascades remains unknown. Here, we report the identification of a differentially phosphorylated MAP kinase kinase kinase that also interacts with FLS2. Using targeted proteomics and functional analysis, we show that MKKK7 negatively regulates flagellin‐triggered signaling and basal immunity and this requires phosphorylation of MKKK7 on specific serine residues. MKKK7 attenuates MPK6 activity and defense gene expression. Moreover, MKKK7 suppresses the reactive oxygen species burst downstream of FLS2, suggesting that MKKK7‐mediated attenuation of FLS2 signaling occurs through direct modulation of the FLS2 complex. 相似文献
2.
Bowirrat A Chen TJ Oscar-Berman M Madigan M Chen AL Bailey JA Braverman ER Kerner M Giordano J Morse S Downs BW Waite RL Fornari F Armaly Z Blum K 《Molecular neurobiology》2012,45(2):298-313
Executive functions are processes that act in harmony to control behaviors necessary for maintaining focus and achieving outcomes. Executive dysfunction in neuropsychiatric disorders is attributed to structural or functional pathology of brain networks involving prefrontal cortex (PFC) and its connections with other brain regions. The PFC receives innervations from different neurons associated with a number of neurotransmitters, especially dopamine (DA). Here we review findings on the contribution of PFC DA to higher-order cognitive and emotional behaviors. We suggest that examination of multifactorial interactions of an individual's genetic history, along with environmental risk factors, can assist in the characterization of executive functioning for that individual. Based upon the results of genetic studies, we also propose genetic mapping as a probable diagnostic tool serving as a therapeutic adjunct for augmenting executive functioning capabilities. We conclude that preservation of the neurological underpinnings of executive functions requires the integrity of complex neural systems including the influence of specific genes and associated polymorphisms to provide adequate neurotransmission. 相似文献
3.
A. Dutour P. Giraud J. Y. Maltese D. Becquet G. Pesce P. Salers LH. Ouafik M. Renard C. Oliver 《Peptides》1990,11(6):1081-1085
The TRH secretory responsiveness of the pancreatic islet cell clusters from newborn rat in organ culture was studied. Basal TRH secretion was stable over a 9-day period. The response to various secretagogues was tested on day 4. TRH secretion was stimulated by high potassium-induced depolarization and also through both cAMP and protein kinase-C dependent pathways. Like insulin, TRH release was stimulated by glucose and arginine and inhibited by somatostatin. These data suggest the existence of a common mechanism for TRH and insulin secretion by the pancreatic β-cells. 相似文献
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William B. Inwood Jason A. Hall Kwang-Seo Kim Lusine Demirkhanyan David Wemmer Helen Zgurskaya Sydney Kustu 《Genetics》2009,183(4):1327-1340
The Escherichia coli ammonium channel AmtB is a trimer in which each monomer carries a pore for substrate conduction and a cytoplasmic C-terminal extension of ∼25 residues. Deletion of the entire extension leaves the protein with intermediate activity, but some smaller lesions in this region completely inactivate AmtB, as do some lesions in its cytoplasmic loops. We here provide genetic evidence that inactivation depends on the essential protease HflB, which appears to cause inactivation not as a protease but as a chaperone. Selection for restored function of AmtB is a positive selection for loss of the ATPase/chaperone activity of HflB and reveals that the conditional lethal phenotype for hflB is cold sensitivity. Deletion of only a few residues from the C terminus of damaged AmtB proteins seems to prevent HflB from acting on them. Either yields the intermediate activity of a complete C-terminal deletion. HflB apparently “tacks” damaged AmtB tails to the adjacent monomers. Knowing that HflB has intervened is prerequisite to determining the functional basis for AmtB inactivation.Amt proteins concentrate the hydrated gas NH4+ against a gradient and appear to be “active” channels (Andrade and Einsle 2007; Fong et al. 2007; Ludewig et al. 2007). Each monomer of the trimer carries a pore for substrate conduction and a C-terminal extension of variable length. The ordered C terminus of Escherichia coli AmtB is a long α-helix interrupted in the middle by a sharp kink, a fold very similar to that of the C-terminal region of Amt-1 from Archaeoglobus fulgidis (Andrade et al. 2005). The C terminus binds precisely to short cytoplasmic loop regions within the monomer to which it is covalently attached and also the adjacent monomer. It completes the cytoplasmic vestibule of the adjacent monomer to link the two (Conroy et al. 2007; Gruswitz et al. 2007). Deletion of the entire C terminus of E. coli AmtB yields a trimeric form of the protein with partial activity (Coutts et al. 2002; Severi et al. 2007): Uptake of [14C]methylammonium by a strain carrying AmtBΔC-term is between that of wild type and an amtB null strain.In organisms that are sensitive to the ammonium analog methylammonium, selection for resistance yields lesions in Amt proteins (Monahan et al. 2002; J. Hsu, W. B. Inwood and S. Kustu, unpublished results). These include some lesions that change residues in the C-terminal kink. Hence we introduced changes into the kink of the E. coli AmtB protein. All three that we tried—G393A, L394A, and the combination of the two—completely inactivated the protein, indicating that something had occurred beyond loss of function of the C terminus (Coutts et al. 2002; Severi et al. 2007). Likewise, we changed charged residues in the cytoplasmic loops of AmtB to alanine and this, too, inactivated the protein in several cases. By selecting for growth at NH3 concentrations <50 nm, where unmediated diffusion is limiting, we isolated strains carrying a large number of mutations that suppressed the growth defect caused by these C-terminal and loop lesions. This work characterizes the intragenic suppressor mutations that affected the C terminus of AmtB, which were about a quarter of the total, and all of the extragenic suppressor mutations, which were ∼40%. It provides genetic evidence that the protease/chaperone HflB attempts to fold damaged C termini unsuccessfully and that this results in loss of AmtB activity. In the absence of intervention by HflB, the mutant C termini mimic a C-terminal delete.HflB (also called FtsH, which is unfortunately a misnomer because the hflB lesion was not responsible for the filamentation that was observed) is a membrane-bound protease that is the only essential ATP-dependent protease in E. coli (Ito and Akiyama 2005). It acts as a processive endopeptidase to release peptides of ∼20 residues. To digest inner-membrane proteins, it requires an N- or C-terminal cytoplasmic extension of about this length. HflB is divided into three regions: an N-terminal membrane-bound region containing two transmembrane segments separated by a large periplasmic loop (residues 1–143), an ATPase segment (AAA+ class; residues 144–398), and an unusual metalloprotease segment (residues 399–649) (Krzywda et al. 2002; Ito and Akiyama 2005; Bieniossek et al. 2006). Although the conditional lethal phenotype for hflB was long thought to be heat sensitivity, this has been questioned (Ogura et al. 1999). A deletion of hflB is tolerated in the presence of a suppressor mutation in fabZ that increases FabZ activity and restores the balance between phospholipid and lipopolysaccharide synthesis. The deletion is likewise tolerated in lpxA or lpxD backgrounds that decrease lipopolysacharide synthesis. HflB has been considered by some a charonin (Schumann 1999; Ito and Akiyama 2005), but there are few specific reports of its chaperone activity, and it is known to have difficulty unfolding proteins that are thermodynamically stable (Herman et al. 2003). 相似文献
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Attempts to eliminate Sarcoptes scabiei var. suis were made in 2 naturally infested sow herds, by intramuscular (IM) injection of doramectin (Dectomax®, Pfizer, New York, USA). A single injection strategy was used. In one of the herds, the environment was treated with an acaricide following dry cleaning of floors, walls and equipment. In the second herd, no environmental treatment was performed. Results were measured by skin lesion scoring, ear scrapings to show Sarcoptes scabiei var. suis, and calculating rubbing index throughout the observation period of 20 months following treatment. Skin lesion scores decreased and stayed low following treatment for the entire observation period. Live Sarcoptes scabiei var. suis mites were isolated prior to treatment from both herds, but not following treatment. Rubbing index decreased following treatment, but was occasionally at or above 0.4. The results of these studies indicate that elimination of Sarcoptes scabiei var. suis from 2 naturally infested herds was successful, using doramectin in a single injection strategy. Precautions must be taken to ensure adequate dosing of every pig, and to avoid reinfestation due to poor biosecurity. 相似文献
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Using a shore-based station we monitored the position of sperm whales (Physeter macrocephalus) within the Kaikoura submarine canyon from 2010 to 2012. We tracked sperm whales using a theodolite station for a total of 290 days. We extracted the distance from the nearest coast, the depth and the bathymetric slope using ArcGIS 10.1. We estimated the seasonal spatial distribution of sperm whales using general additive models. The distribution varied significantly between seasons; individuals were found in deeper water and further offshore in the spring than in winter. This study improved our understanding of the variability of sperm whale distribution patterns off Kaikoura. We determined that the distribution was linked to the bathymetric features and we hypothesized that whales adapted their use of the submarine canyon in relation to food aggregation. We would encourage further studies to evaluate the sperm whale relationship with oceanographic variables off Kaikoura. 相似文献
8.
Swapna Asuthkar Lusine Demirkhanyan Xiaohui Sun Pia A. Elustondo Vivek Krishnan Padmamalini Baskaran Kiran Kumar Velpula Baskaran Thyagarajan Evgeny V. Pavlov Eleonora Zakharian 《The Journal of biological chemistry》2015,290(5):2670-2688
Testosterone is a key steroid hormone in the development of male reproductive tissues and the regulation of the central nervous system. The rapid signaling mechanism induced by testosterone affects numerous behavioral traits, including sexual drive, aggressiveness, and fear conditioning. However, the currently identified testosterone receptor(s) is not believed to underlie the fast signaling, suggesting an orphan pathway. Here we report that an ion channel from the transient receptor potential family, TRPM8, commonly known as the cold and menthol receptor is the major component of testosterone-induced rapid actions. Using cultured and primary cell lines along with the purified TRPM8 protein, we demonstrate that testosterone directly activates TRPM8 channel at low picomolar range. Specifically, testosterone induced TRPM8 responses in primary human prostate cells, PC3 prostate cancer cells, dorsal root ganglion neurons, and hippocampal neurons. Picomolar concentrations of testosterone resulted in full openings of the purified TRPM8 channel in planar lipid bilayers. Furthermore, acute applications of testosterone on human skin elicited a cooling sensation. Our data conclusively demonstrate that testosterone is an endogenous and highly potent agonist of TRPM8, suggesting a role of TRPM8 channels well beyond their well established function in somatosensory neurons. This discovery may further imply TRPM8 channel function in testosterone-dependent behavioral traits. 相似文献
9.
Thomas Fleischer Arnoldo Frigessi Kevin C Johnson Hege Edvardsen Nizar Touleimat Jovana Klajic Margit LH Riis Vilde D Haakensen Fredrik W?rnberg Bj?rn Naume ?slaug Helland Anne-Lise B?rresen-Dale J?rg Tost Brock C Christensen Vessela N Kristensen 《Genome biology》2014,15(8)
Background
Ductal carcinoma in situ (DCIS) of the breast is a precursor of invasive breast carcinoma. DNA methylation alterations are thought to be an early event in progression of cancer, and may prove valuable as a tool in clinical decision making and for understanding neoplastic development.Results
We generate genome-wide DNA methylation profiles of 285 breast tissue samples representing progression of cancer, and validate methylation changes between normal and DCIS in an independent dataset of 15 normal and 40 DCIS samples. We also validate a prognostic signature on 583 breast cancer samples from The Cancer Genome Atlas. Our analysis reveals that DNA methylation profiles of DCIS are radically altered compared to normal breast tissue, involving more than 5,000 genes. Changes between DCIS and invasive breast carcinoma involve around 1,000 genes. In tumors, DNA methylation is associated with gene expression of almost 3,000 genes, including both negative and positive correlations. A prognostic signature based on methylation level of 18 CpGs is associated with survival of breast cancer patients with invasive tumors, as well as with survival of patients with DCIS and mixed lesions of DCIS and invasive breast carcinoma.Conclusions
This work demonstrates that changes in the epigenome occur early in the neoplastic progression, provides evidence for the possible utilization of DNA methylation-based markers of progression in the clinic, and highlights the importance of epigenetic changes in carcinogenesis.Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0435-x) contains supplementary material, which is available to authorized users. 相似文献10.
Kim D Baas Maarten WJ Koeter Henk C van Weert Peter Lucassen Claudi LH Bockting Karin A Wittkampf Aart H Schene 《Trials》2010,11(1):1-6