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Central Regulator (central + regulator)
Selected AbstractsHepcidin , central regulator of iron metabolismEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 1 2007Valeriu Atanasiu Abstract The knowledge about mammalian iron metabolism has advanced dramatically over the past decades. Studies of genetics, biochemistry and molecular biology allowed us the identification and characterization of many of the molecules involved in regulation of iron homeostasis. Important progresses were made after the discovery in 2000 of a small peptide , hepcidin , that has been proved to play a central role in orchestration on iron metabolism also providing a link between iron metabolism and inflammation and innate immunity. Hepcidin directly interacts with ferroportin (FPN), the only known mammalian iron exporter, which is expressed by enterocytes, macrophages and hepatocytes. The direct hepcidin,FPN interaction allows an adaptative response from the body in situations that alter normal iron homeostasis (hypoxia, anemia, iron deficiency, iron overload, and inflammation). [source] dye (arc) mutants: insights into an unexplained phenotype and its suppression by the synthesis of poly (3-hydroxybutyrate) in Escherichia coli recombinantsFEMS MICROBIOLOGY LETTERS, Issue 1 2006Jimena A. Ruiz Abstract arcA codes for a central regulator in Escherichia coli that responds to redox conditions of growth. Mutations in this gene, originally named dye, confer sensitivity to toluidine blue and other redox dyes. However, the molecular basis for the dye-sensitive phenotype has not been elucidated. In this work, we show that toluidine blue redirects electrons to O2 and causes an increase in the generation of reactive O2 species (ROS). We also demonstrate that synthesis of poly (3-hydroxybutyrate) suppresses the Dye phenotype in E. coli recombinants, as the capacity to synthesize the polymer reduces sensitivity to toluidine blue, O2 consumption and ROS production levels. [source] A variant of the myosin light chain kinase gene is associated with severe asthma in African AmericansGENETIC EPIDEMIOLOGY, Issue 4 2007Carlos Flores Abstract Asthma is a complex phenotype influenced by environmental and genetic factors for which severe irreversible structural airway alterations are more frequently observed in African Americans. In addition to a multitude of factors contributing to its pathobiology, increased amounts of myosin light chain kinase (MLCK), the central regulator of cellular contraction, have been found in airway smooth muscle from asthmatics. The gene encoding MLCK (MYLK) is located in 3q21.1, a region noted by a number of genome-wide studies to show linkage with asthma and asthma-related phenotypes. We studied 17 MYLK genetic variants in European and African Americans with asthma and severe asthma and identified a single non-synonymous polymorphism (Pro147Ser) that was almost entirely restricted to African populations and which was associated with severe asthma in African Americans. These results remained highly significant after adjusting for proportions of ancestry estimated using 30 unlinked microsatellites (adjusted odds ratio: 1.76 [95% confidence interval, CI: 1.17,2.65], p = 0.005). Since all common HapMap polymorphisms in ,500,kb contiguous regions have low-to-moderate linkage disequilibrium with Pro147Ser, we speculate that this polymorphism is causally related to the severe asthma phenotype in African Americans. The association of this polymorphism, located in the N-terminal region of the non-muscle MLCK isoform, emphasizes the potential importance of the vascular endothelium, a tissue in which MLCK is centrally involved in multiple aspects of the inflammatory response, in the pathogenesis of severe asthma. This finding also offers a possible genetic explanation for some of the more severe asthma phenotype observed in African American asthmatics. Genet Epidemiol 2007. © 2007 Wiley-Liss, Inc. [source] Differentiation therapy of hepatocellular carcinoma in mice with recombinant adenovirus carrying hepatocyte nuclear factor-4, gene,HEPATOLOGY, Issue 5 2008Chuan Yin Previous studies have shown that hepatocyte nuclear factor-4, (HNF4,) is a central regulator of differentiated hepatocyte phenotype and forced expression of HNF4, could promote reversion of tumors toward a less invasive phenotype. However, the effect of HNF4, on cancer stem cells (CSCs) and the treatment of hepatocellular carcinoma (HCC) with HNF4, have not been reported. In this study, an adenovirus-mediated gene delivery system, which could efficiently transfer and express HNF4,, was generated to determine its effect on hepatoma cells (Hep3B and HepG2) in vitro and investigate the anti-tumor effect of HNF4, in mice. Our results demonstrated that forced re-expression of HNF4, induced the differentiation of hepatoma cells into hepatocytes, dramatically decreased "stemness" gene expression and the percentage of CD133+ and CD90+ cells, which are considered as cancer stem cells in HCC. Meanwhile, HNF4, reduced cell viability through inducing apparent apoptosis in Hep3B, while it induced cell cycle arrest and cellular senescence in HepG2. Moreover, infection of hepatoma cells by HNF4, abolished their tumorigenesis in mice. Most interestingly, systemic administration of adenovirus carrying the HNF4, gene protected mice from liver metastatic tumor formation, and intratumoral injection of HNF4, also displayed significant antitumor effects on transplanted tumor models. Conclusion: The striking suppression effect of HNF4, on tumorigenesis and tumor development is attained by inducing the differentiation of hepatoma cells,especially CSCs,into mature hepatocytes, suggesting that differentiation therapy with HNF4, may be an effective treatment for HCC patients. Our study also implies that differentiation therapy may present as one of the best strategies for cancer treatment through the induction of cell differentiation by key transcription factors. (HEPATOLOGY 2008.) [source] Altered signalling from germline to intestine pushes daf-2;pept-1 Caenorhabditis elegans into extreme longevityAGING CELL, Issue 4 2010Britta Spanier Summary The insulin-like signalling pathway is a central regulator of development, metabolism, stress resistance and lifespan in eukaryotes. Caenorhabditis elegans daf-2(e1370) animals with a loss-of-function mutation in the insulin-like receptor live twice as long as wild-type animals, and the additional knockout of the intestinal di- and tripeptide transporter pept-1 further increases lifespan by 60%. In assessing the underlying molecular mechanisms for this phenomenon, microarray-based transcriptome data sets of daf-2(e1370) and daf-2(e1370);pept-1(lg601) animals were compared with a focus on genes that showed significantly higher changes in expression levels in daf-2;pept-1 than in daf-2. We identified 187 genes with at least fourfold decreased transcript levels and 170 with more than a fourfold increase. A large fraction of the down-regulated genes encode proteins involved in germline proliferation and reproduction. The DAF-9/DAF-12 signalling cascade was identified as a prime pathway that mediates the longevity of daf-2;pept-1 with a strict dependance on DAF-16. Loss of DAF-9/DAF-12 or KRI-1 reduces the lifespan of daf-2;pept-1 to that of the daf-2 mutant. Amongst the DAF-16 target genes, numerous enzymes involved in the defence of reactive oxygen species were with increased expression level in daf-2;pept-1. On a functional level, it was demonstrated that amongst those, a high de novo synthesis rate of glutathione is most important for the longevity phenotype of this strain. Taken together, a close interdependence of endocrine hormone signalling from germline to intestine was identified as an essential element in the control of the extreme longevity of C. elegans lacking a proper function of the insulin receptor and lacking the intestinal peptide transporter. [source] Effects of Alcohol Consumption on Iron Metabolism in Mice with Hemochromatosis MutationsALCOHOLISM, Issue 1 2007Jonathan M. Flanagan Background: Alcoholic liver disease is associated with increased hepatic iron accumulation. The liver-derived peptide hepcidin is the central regulator of iron homeostasis and recent animal studies have demonstrated that exposure to alcohol reduces hepcidin expression. This down-regulation of hepcidin in vivo implies that disturbed iron sensing may contribute to the hepatosiderosis seen in alcoholic liver disease. Alcohol intake is also a major factor in expression of the hemochromatosis phenotype in patients homozygous for the C282Y mutation of the HFE gene. Methods: To assess the effect of alcohol in mice with iron overload, alcohol was administered to mice with disrupted Hfe and IL-6 genes and Tfr2 mutant mice and their respective 129x1/SvJ, C57BL/6J, and AKR/J wild-type congenic strains. Iron absorption, serum iron levels, and hepcidin expression levels were then measured in these mice compared with water-treated control mice. Results: Alcohol was shown to have a strain-specific effect in 129x1/SvJ mice, with treated 129x1/SvJ mice showing a significant increase in iron absorption, serum iron levels, and a corresponding decrease in hepcidin expression. C57BL/6J and AKR/J strain mice showed no effect from alcohol treatment. 129x1/SvJ mice heterozygous or homozygous for the Hfe knockout had a diminished response to alcohol. All 3 strains were shown to have high blood alcohol levels. Conclusions: The effect of alcohol on iron homeostasis is dependent on the genetic background in mice. In an alcohol-susceptible strain, mutation of the Hfe gene diminished the response of the measured iron indices to alcohol treatment. This indicates that either maximal suppression of hepcidin levels had already occurred as a result of the Hfe mutation or that Hfe was a component of the pathway utilized by EtOH in suppressing hepcidin production and increasing iron absorption. [source] Inherited defects of coagulation factor V: the hemorrhagic sideJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 1 2006R. ASSELTA Summary., Coagulation factor V (FV) is the protein cofactor required in vivo for the rapid generation of thrombin catalyzed by the prothrombinase complex. It also represents a central regulator in the early phases of blood clot formation, as it contributes to the anticoagulant pathway by participating in the downregulation of factor VIII activity. Conversion of precursor FV to either a procoagulant or anticoagulant cofactor depends on the local concentration of procoagulant and anticoagulant enzymes, so that FV may be regarded as a daring tight-rope walker gently balancing opposite forces. Given this dual role, genetic defects in the FV gene may result in opposite phenotypes (hemorrhagic or thrombotic). Besides a concise description on the structural, procoagulant and anticoagulant properties of FV, this review will focus on bleeding disorders associated with altered levels of this molecule. Particular attention will be paid to the mutational spectrum of type I FV deficiency, which is characterized by a remarkable genetic heterogeneity and by an uneven distribution of mutations throughout the FV gene. [source] SRFR1, a suppressor of effector-triggered immunity, encodes a conserved tetratricopeptide repeat protein with similarity to transcriptional repressorsTHE PLANT JOURNAL, Issue 1 2009Soon Il Kwon Summary Effector-triggered immunity provides plants with strong protection from pathogens. However, this response has the potential to be highly deleterious to the host and needs to be tightly controlled. The molecular mechanisms in the plant that regulate the balance between activation and suppression of resistance are not fully understood. Previously, we identified Arabidopsis suppressor of rps4-RLD 1 (srfr1) mutants with enhanced resistance to the bacterial effector AvrRps4. These mutants were recessive and retained full susceptibility to virulent bacteria, suggesting that SRFR1 functions as a negative regulator and that AvrRps4-triggered immunity was specifically enhanced in the mutants. Consistent with this, we show here that the response to flagellin, an elicitor of basal resistance, is unaltered in srfr1-1. In contrast, resistance to AvrRps4 in srfr1-1 requires EDS1, a central regulator of effector-triggered immunity via multiple resistance genes. SRFR1 is a single-copy gene encoding a pioneer tetratricopeptide repeat protein conserved between plants and animals. The SRFR1 tetratricopeptide repeat domain shows sequence similarity to those of transcriptional repressors in Saccharomyces cerevisiae and Caenorhabditis elegans. Indeed, a sub-pool of SRFR1 transiently expressed in Nicotiana benthamiana leaf cells localizes to the nucleus. Identification of SRFR1 may therefore provide insight into the regulation of the transcriptional reprogramming that is activated by effector-triggered immunity. [source] Abiotic stress and plant responses from the whole vine to the genesAUSTRALIAN JOURNAL OF GRAPE AND WINE RESEARCH, Issue 2010G.R. CRAMER Abstract Drought, salinity and extreme temperatures significantly limit the distribution of grapes around the world. In this review, the literature of grape responses to abiotic stress with particular reference to whole plant and molecular responses observed in recent studies is discussed. A number of short-term and long-term studies on grapevine shoots and berries have been conducted using a systems biology approach. Transcripts, proteins and metabolites were profiled. Water deficit, salinity and chilling altered the steady-state abundance of a large number of transcripts. Common responses to these stresses included changes in hormone metabolism, particularly abscisic acid (ABA), photosynthesis, growth, transcription, protein synthesis, signalling and cellular defences. Some of the transcriptional changes induced by stress were confirmed by proteomic and metabolomic analyses. More than 2000 genes were identified whose transcript abundance was altered by both water deficit and ABA. Different gene sets were used to map molecular pathways regulated by ABA, water deficit, salinity and chilling in grapevine. This work supports the hypothesis that ABA is a central regulator of abiotic stress tolerance mechanisms. ABA affects signalling pathways that trigger important molecular activities involving metabolism, transcription, protein synthesis, and cellular defence and also regulates important physiological responses such as stomatal conductance, photoprotection and growth. Systems biology approaches are providing more comprehensive understanding of the complex plant responses to abiotic stress. The molecular sets generated from mapping the ABA-inducible stress responses provide numerous targets for genetic and cultural manipulation for improved plant protection and grape quality. [source] Intracellular parasitism with Toxoplasma gondii stimulates mammalian-target-of-rapamycin-dependent host cell growth despite impaired signalling to S6K1 and 4E-BP1CELLULAR MICROBIOLOGY, Issue 6 2009Yubao Wang Summary The Ser/Thr kinase mammalian-target-of-rapamycin (mTOR) is a central regulator of anabolism, growth and proliferation. We investigated the effects of Toxoplasma gondii on host mTOR signalling. Toxoplasma invasion of multiple cell types rapidly induced sustained mTOR activation that was restricted to infected cells, as determined by rapamycin-sensitive phosphorylation of ribosomal protein S6; however, phosphorylation of the growth-associated mTOR substrates 4E-BP1 and S6K1 was not detected. Infected cells still phosphorylated S6K1 and 4E-BP1 in response to insulin, although the S6K1 response was blunted. Parasite-induced S6 phosphorylation was independent of S6K1 and did not require activation of canonical mTOR-inducing pathways mediated by phosphatidylinositol 3-kinase,Akt and ERK. Host mTOR was localized in a vesicular pattern surrounding the parasitophorous vacuole, suggesting potential activation by phosphatidic acid in the vacuolar membrane. In spite of a failure to phosphorylate 4E-BP1 and S6K1, intracellular T. gondii triggered host cell cycle progression in an mTOR-dependent manner and progression of infected cells displayed increased sensitivity to rapamycin. Moreover, normal cell growth was maintained during parasite-induced cell cycle progression, as indicated by total cellular S6 levels. The Toxoplasma -infected cell provides a unique example of non-canonical mTOR activation supporting growth that is independent of signalling through either S6K1 or 4E-BP1. [source] Hip geometry variation is associated with bone mineralization pathway gene variants: The framingham studyJOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2010Ching-Lung Cheung Abstract Mineralization of bone matrix is an important process in bone formation; thus defects in mineralization have been implicated in bone mineral density (BMD) and bone structure alterations. Three central regulators of phosphate balance, ALPL, ANKH, and ENPP1, are central in the matrix mineralization process; therefore, the genes encoding them are considered important candidates genes for BMD and bone geometry. To test for an association between these three candidate genes and BMD and bone geometry traits, 124 informative single-nucleotide polymorphisms (SNPs) were selected and genotyped in 1513 unrelated subjects from the Framingham offspring cohort. Initial results showed that SNP rs1974201 in the gene ENPP1 was a susceptibility variant associated with several hip geometric indices, with the strongest p value of 3.8,×,10,7 being observed for femoral neck width. A few modest associations were observed between SNPs in or near ALPL and several bone traits, but no association was observed with ANKH. The association signals observed for SNPs around rs1974201 were attenuated after conditional analysis on rs1974201. Transcription factor binding-site prediction revealed that the HOXA7 binding site was present in the reference sequence with the major allele, whereas this potential binding site is lost in the sequence with the minor allele of rs1974201. In conclusion, we found evidence for association of bone geometry variation with an SNP in ENPP1, a gene in the mineralization pathway. The alteration of a binding site of the deregulator of extracellular matrix HOXA7 warrants further investigation. © 2010 American Society for Bone and Mineral Research [source] Examining the Intersection of Sex and Stress in Modelling Neuropsychiatric DisordersJOURNAL OF NEUROENDOCRINOLOGY, Issue 4 2009N. Goel Sex-biased neuropsychiatric disorders, including major depressive disorder and schizophrenia, are the major cause of disability in the developed world. Elevated stress sensitivity has been proposed as a key underlying factor in disease onset. Sex differences in stress sensitivity are associated with corticotrophin-releasing factor (CRF) and serotonin neurotransmission, which are important central regulators of mood and coping responses. To elucidate the underlying neurobiology of stress-related disease predisposition, it is critical to develop appropriate animal models of stress pathway dysregulation. Furthermore, the inclusion of sex difference comparisons in stress responsive behaviours, physiology and central stress pathway maturation in these models is essential. Recent studies by our laboratory and others have begun to investigate the intersection of stress and sex where the development of mouse models of stress pathway dysregulation via prenatal stress experience or early-life manipulations has provided insight into points of developmental vulnerability. In addition, examination of the maturation of these pathways, including the functional importance of the organisational and activational effects of gonadal hormones on stress responsivity, is essential for determination of when sex differences in stress sensitivity may begin. In such studies, we have detected distinct sex differences in stress coping strategies where activational effects of testosterone produced females that displayed male-like strategies in tests of passive coping, but were similar to females in tests of active coping. In a second model of elevated stress sensitivity, male mice experiencing prenatal stress early in gestation showed feminised physiological and behavioural stress responses, and were highly sensitive to a low dose of selective serotonin reuptake inhibitors. Analyses of expression and epigenetic patterns revealed changes in CRF and glucocorticoid receptor genes in these mice. Mechanistically, stress early in pregnancy produced a significant sex-dependent effect on placental gene expression that was supportive of altered foetal transport of key growth factors and nutrients. These mouse models examining alterations and hormonal effects on development of stress pathways provide necessary insight into how specific stress responses can be reprogrammed early in development resulting in sex differences in stress sensitivity and neuropsychiatric disease vulnerability. [source] Overexpression of EgROP1, a Eucalyptus vascular-expressed Rac-like small GTPase, affects secondary xylem formation in Arabidopsis thalianaNEW PHYTOLOGIST, Issue 4 2009Camille Foucart Summary ,,To better understand the genetic control of secondary xylem formation in trees we analysed genes expressed during Eucalyptus xylem development. ,Using eucalyptus xylem cDNA libraries, we identified EgROP1, a member of the plant ROP family of Rho-like GTPases. These signalling proteins are central regulators of many important processes in plants, but information on their role in xylogenesis is scarce. ,,Quantitative real-time reverse-transcriptase polymerase chain reaction (qRT-PCR) confirmed that EgROP1 was preferentially expressed in the cambial zone and differentiating xylem in eucalyptus. Genetic mapping performed in a eucalyptus breeding population established a link between EgROP1 sequence polymorphisms and quantitative trait loci (QTLs) related to lignin profiles and fibre morphology. Overexpression of various forms of EgROP1 in Arabidopsis thaliana altered anisotropic cell growth in transgenic leaves, but most importantly affected vessel element and fibre growth in secondary xylem. Patches of fibre-like cells in the secondary xylem of transgenic plants showed changes in secondary cell wall thickness, lignin and xylan composition. ,,These results suggest a role for EgROP1 in fibre cell morphology and secondary cell wall formation making it a good candidate gene for marker-based selection of eucalyptus trees. [source] Reactive oxygen signaling and abiotic stressPHYSIOLOGIA PLANTARUM, Issue 3 2008Gad Miller Reactive oxygen species (ROS) play a dual role in plant biology acting on the one hand as important signal transduction molecules and on the other as toxic by-products of aerobic metabolism that accumulate in cells during different stress conditions. Because of their toxicity as well as their important signaling role, the level of ROS in cells is tightly controlled by a vast network of genes termed the ,ROS gene network'. Using mutants deficient in key ROS-scavenging enzymes, we have defined a signaling pathway that is activated in cells in response to ROS accumulation. Interestingly, many of the key players in this pathway, including different zinc finger proteins and WRKY transcription factors, are also central regulators of abiotic stress responses involved in temperature, salinity and osmotic stresses. Here, we describe our recent findings and discuss how ROS integrate different signals originating from different cellular compartments during abiotic stress. [source] | |||||||||||||||||||||||||