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Novel Regulator (novel + regulator)
Selected AbstractsKisspeptin: A Novel Regulator of Reproductive FunctionJOURNAL OF NEUROENDOCRINOLOGY, Issue 8 2008W. S. Dhillo Young Neuroendocrinologists Prize Reviews Michael Harbuz Young Investigator Prize Lecture The UK and international neuroendocrine community was deeply shocked and saddened the unbelievably premature death of Michael Harbuz in Bristol in 2006. Mick was a superb friend and colleague, and played a huge part in the development and activities of the British Neuroendocrine Group/British Society for Neuroendocrinology (BSN), serving as both Membership Secretary and Treasurer between 1999 and 2004. Mick was a leader in the field of neuroendocrine,immune interactions, and brought a great deal of charisma, humour and ability to meetings and conferences. He was also a passionate and committed supporter of the progress of young researchers and of their participation in neuroendocrine events. He recognised that today's postgraduate students and postdoctoral research fellows are tomorrow's neuroendocrine researchers, be it in academia, the health services or industry. To recognise Mick's great commitment to and enthusiasm for postgraduate education both in the University of Bristol and in the BSN, we decided to honour and remember him by instituting the ,Michael Harbuz Young Investigator Prize Lecture' to be delivered annually. Dr Waljit Dhillo from Imperial College London was the inaugural recipient of this award, and presented his lecture at the Annual Meeting of the BSN in Nottingham in September 2007, upon which this review is based. Recent evidence demonstrates that the neuropeptide kisspeptin and its receptor, GPR54, have a fundamental role in initiating the onset of puberty and are important in regulating reproductive function. This review discusses the evidence available from animals and humans demonstrating that kisspeptin potently stimulates the release of gonadotrophins by stimulating the release of gonadotrophin-releasing hormone and that a lack of kisspeptin or GPR54 results in reproductive failure. [source] ORIGINAL ARTICLE: Calcineurin/NFAT Pathway: A Novel Regulator of ParturitionAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 1 2009Chisa Tabata Problem, The oxytocin (OT),oxytocin receptor (OTR) system plays an important role in mammalian parturition. However, we found OTR-deficient (OTRKO) mice are fertile and deliver at term without birth defects, thus alternative pathways inducing parturition can be hypothesized. Methods of study, We tested the gene expression profile of OTRKO mice using suppressive subtractive hybridization, and focused on the calcineurin/nuclear factor of activated T cells (NFAT) pathway. We examined the expression and localization of this pathway in mouse parturition. Results, Calcineurin and NFATc1 were detected in the decidua of pregnant uteri at term using immunohistochemistry (IHC). We identified higher activation levels of NFATc1 in wild type (WT) than in OTRKO mice and increased calcineurin A and NFATc1 mRNA levels during pregnancy. Moreover, injection of FK506, the inhibitor of this pathway, prolonged the delivery of the first pup. Conclusion, Our findings suggested that the calcineurin/NFAT pathway might play a substantial role in initiation of labor. [source] Identification of Novel Regulators Associated With Early-Phase Osteoblast Differentiation,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2004Diana S de Jong Abstract Key regulatory components of the BMP-induced osteoblast differentiation cascade remain to be established. Microarray and subsequent expression analyses in mice identified two transcription factors, Hey1 and Tcf7, with in vitro and in vivo expression characteristics very similar to Cbfa1. Transfection studies suggest that Tcf7 modulates BMP2-induced osteoblast differentiation. This study contributes to a better definition of the onset of BMP-induced osteoblast differentiation. Introduction: Elucidation of the genetic cascade guiding mesenchymal stem cells to become osteoblasts is of extreme importance for improving the treatment of bone-related diseases such as osteoporosis. The aim of this study was to identify regulators of the early phases of bone morphogenetic protein (BMP)2-induced osteoblast differentiation. Materials and Methods: Osteoblast differentiation of mouse C2C12 cells was induced by treatment with BMP2, and regulation of gene expression was studied during the subsequent 24 h using high-density microarrays. The regulated genes were grouped by means of model-based clustering, and protein functions were assigned. Real-time quantitative RT-PCR analysis was used to validate BMP2-induced gene expression patterns in C2C12 cells. Osteoblast specificity was studied by comparing these expression patterns with those in C3H10T1/2 and NIH3T3 cells under similar conditions. In situ hybridization of mRNA in embryos at embryonic day (E)14.5 and E16.5 of gestation and on newborn mouse tails were used to study in vivo expression patterns. Cells constitutively expressing the regulated gene Tcf7 were used to investigate its influence on BMP-induced osteoblast differentiation. Results and Conclusions: A total of 184 genes and expressed sequence tags (ESTs) were differentially expressed in the first 24 h after BMP2 treatment and grouped in subsets of immediate early, intermediate early, and late early response genes. Signal transduction regulatory factors mainly represented the subset of immediate early genes. Regulation of expression of these genes was direct, independent of de novo protein synthesis and independent of the cell type studied. The intermediate early and late early genes consisted primarily of genes related to processes that modulate morphology, basement membrane formation, and synthesis of extracellular calcified matrix. The late early genes require de novo protein synthesis and show osteoblast specificity. In vivo and in vitro experiments showed that the transcription factors Hey1 and Tcf7 exhibited expression characteristics and cell type specificity very similar to those of the osteoblast specific transcription factor Cbfa1, and constitutive expression of Tcf7 in C2C12 cells differentially regulated osteoblast differentiation marker genes. [source] Transcriptional control of the pvdS iron starvation sigma factor gene by the master regulator of sulfur metabolism CysB in Pseudomonas aeruginosaENVIRONMENTAL MICROBIOLOGY, Issue 6 2010Francesco Imperi Summary In the Gram-negative pathogen Pseudomonas aeruginosa, the alternative sigma factor PvdS acts as a key regulator of the response to iron starvation. PvdS also controls P. aeruginosa virulence, as it drives the expression of a large set of genes primarily implicated in biogenesis and transport of the pyoverdine siderophore and synthesis of extracellular factors, such as protease PrpL and exotoxin A. Besides the ferric uptake regulatory protein Fur, which shuts off pvdS transcription under iron-replete conditions, no additional regulatory factor(s) controlling the pvdS promoter activity have been characterized so far. Here, we used the promoter region of pvdS as bait to tentatively capture, by DNA-protein affinity purification, P. aeruginosa proteins that are able to bind specifically to the pvdS promoter. This led to the identification and functional characterization of the LysR-like transcription factor CysB as a novel regulator of pvdS transcription. The CysB protein directly binds to the pvdS promoter in vitro and acts as a positive regulator of PvdS expression in vivo. The absence of a functional CysB protein results in about 50% reduction of expression of PvdS-dependent virulence phenotypes. Given the role of CysB as master regulator of sulfur metabolism, our findings establish a novel molecular link between the iron and sulfur regulons in P. aeruginosa. [source] STAT-1: a novel regulator of apoptosisINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 6 2003Anastasis Stephanou Summary., Extracellular signalling molecules binding to their specific receptors are able to modulate gene expression, leading to changes in development, cell growth and homeostasis. The signal transducers and activators of transcription (STAT) protein family members are among the best studied of the latent cytoplasmic signal-dependent transcription factors. The STAT factors are activated via phosphorylation on the C-terminal domain following cytokine signalling or by various stress-induced stimuli. Recently, STAT-1 has been implicated in modulating pro- and anti-apoptotic genes following several stress-induced responses. These effects are dependent on STAT-1 phosphorylation on serine-727 and require the C-terminal transactivation domain of STAT-1 to enhance its pro-apoptotic effect or inhibit its anti-apoptotic effects. The STAT-1 C-terminal domain has been demonstrated to be important for protein,protein interaction with other transcriptional activators. The reports that STAT-1-deficient mice develop spontaneous and chemically induced tumours more rapidly compared to wild-type mice and that STAT-1-deficient cells are more resistant to agents that induce apoptosis strongly support the argument that STAT-1 acts as a tumour suppressor. [source] Regulation of C-Terminal and Intact FGF-23 by Dietary Phosphate in Men and Women,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2006Sherri-Ann M Burnett MD Abstract FGF-23 is a novel regulator of phosphate metabolism. We studied the regulation of FGF-23 by dietary phosphate in 66 men and women using two assays. Dietary phosphate restriction decreased FGF-23 and loading increased FGF-23 significantly. An assay that measured intact FGF-23 showed the effects of dietary phosphate much more clearly than an assay that also measures presumed biologically inactive fragments. Dietary phosphate is a key regulator of circulating FGF-23; choice of assay is critical when studying FGF-23 physiology. Introduction: Fibroblast growth factor 23 (FGF-23) is a novel phosphaturic factor discovered through genetic studies of patients with renal phosphate wasting disorders. Ablation of the FGF-23 gene in mice reduces renal phosphate excretion and increases serum phosphate, suggesting that FGF-23 is critical for normal phosphate homeostasis. We examined the role of dietary phosphate in the regulation of FGF-23 in humans. Materials and Methods: Sixty-six healthy males and females were randomized to either phosphate-depleted or -loaded diets for 5 days, after a 4-day run-in diet. FGF-23 was measured using an "intact" assay that only detects intact FGF-23 peptide and with a "C-terminal" assay that measures both intact FGF-23 peptide and presumed biologically inactive carboxyl terminal fragments. The main outcome was the within group change in FGF-23 with either phosphate depletion or loading. Results: Using the intact FGF-23 assay, mean FGF-23 area under the curve (AUC) decreased by 9 ± 16% with phosphate depletion (p = 0.0041) and increased by 35 ± 29% with loading (p < 0.0001). Using the C-terminal FGF-23 assay, mean FGF-23 AUC decreased by 8 ± 12% with phosphate depletion (p = 0.0003) and increased by 13 ± 20% with loading (p = 0.0016). Increases in FGF-23 with phosphate loading were greater with the intact assay than with the C-terminal assay (p = 0.0003). Using the intact assay only, FGF-23 was significantly associated with serum phosphate (r = 0.39, p < 0.01), 24-h urinary phosphate (r = 0.47, p < 0.01), fractional excretion of phosphate (r = 0.29, p < 0.01), and 1,25-dihydroxyvitamin D (r = ,0.30, p < 0.01). The association between the assays was weak (r = 0.26, p < 0.01). Conclusions: Dietary phosphate is a key regulator of circulating FGF-23 levels in humans. Additionally, choice of assay is critical when performing physiologic investigations of FGF-23. [source] Regulation of Human Skeletal Stem Cells Differentiation by Dlk1/Pref-1JOURNAL OF BONE AND MINERAL RESEARCH, Issue 5 2004Basem M Abdallah Abstract Dlk-1/Pref-1 was identified as a novel regulator of human skeletal stem cell differentiation. Dlk1/Pref-1 is expressed in bone and cultured osteoblasts, and its constitutive overexpression led to inhibition of osteoblast and adipocyte differentiation of human marrow stromal cells. Introduction: Molecular control of human mesenchymal stem cell (hMSC) differentiation into osteoblasts and adipocytes is not known. In this study, we examined the role of delta-like 1/preadipocyte factor-1 (Dlk1/Pref-1) in regulating the differentiation of hMSCs. Materials and Methods: As a model for hMSCs, we have stably transduced telomerase-immortalized hMSC (hMSC-TERT) with the full length of human Dlk1/Pref-1 cDNA and tested its effect on hMSC growth and differentiation into osteoblasts or adipocytes as assessed by cytochemical staining, FACS analysis, and real time PCR. Ex vivo calvaria organ cultures assay was used to confirm the in vitro effect of Dlk/Pref-1 on bone formation. Results: Dlk1/Pref-1 was found to be expressed in fetal and adult bone, hMSCs, and some osteoblastic cell lines. A retroviral vector containing the human Dlk1/Pref-1 cDNA was used to create a cell line (hMSC-dlk1) expressing high levels of Dlk1/Pref-1 protein. Overexpression of Dlk1/Pref-1 did not affect the proliferation rate of hMSC, but the ability to form mature adipocytes, mineralized matrix in vitro, and new bone formation in neonatal murine calvariae organ cultures was reduced. These effects were associated with inhibition of gene expression markers of late stages of adipocyte (adipocyte fatty acid-binding protein [aP2], peroxisome proliferator-activated receptor-gamma2 [PPAR,2], and adiponectin [APM1]) and osteoblast differentiation (alkaline phosphatase [ALP], collagen type I [Col1], and osteocalcin [OC]). Lineage commitment markers for adipocytes (adipocyte determination and differentiation factor ,1 [ADD1]) and osteoblasts (core binding factor/runt-related binding factor 2 [Cbfa1/Runx2]) were not affected. Conclusion: During hMSC differentiation, Dlk1/Pref-1 maintains the size of the bipotential progenitor cell pool by inhibiting the formation of mature osteoblasts and adipocytes. [source] Identification of the central quorum sensing regulator of virulence in the enteric phytopathogen, Erwinia carotovora: the VirR repressorMOLECULAR MICROBIOLOGY, Issue 1 2006Tom Burr Summary In the Gram-negative phytopathogen, Erwinia carotovora ssp. atroseptica (Eca) virulence depends on the production of a N- (3-oxohexanoyl)- l -homoserine lactone (OHHL) quorum sensing (QS) signal. This work identifies the elusive ,missing link' between QS and virulence in Erwinia. We have identified and characterized a novel regulator of virulence, VirR, in Eca and show that a virR mutation completely restores virulence factor production to an Eca mutant unable to synthesize OHHL. This effect of the virR mutation translates to a restoration of virulence to wild-type levels and thus provides evidence that VirR acts to prevent the production of virulence factors at low cell density. We also show that, in Eca, transcription of virulence genes is controlled by OHHL and that this control is effected through the action of VirR. We also demonstrate that the VirR regulatory pathway is present and functional in both blackleg and soft rotting species of Erwinia. [source] NDRG2 gene expression in B16F10 melanoma cells restrains melanogenesis via inhibition of Mitf expressionPIGMENT CELL & MELANOMA RESEARCH, Issue 6 2008Aeyung Kim Summary NDRG2 (N-myc downstream-regulated gene 2) is a candidate tumor suppressor implicated in control of glioblastoma proliferation and dendritic cell differentiation. The microphthalmia-associated transcription factor (Mitf) plays a crucial role in the melanocyte lineage and in melanoma by controlling survival, differentiation, cell cycle entry and exit, and melanoma metastasis. Identifying upstream regulators of Mitf expression, therefore, remains a key issue. In this study, we aimed to assess whether the candidate tumor suppressor NDRG2 can modulate Mitf expression. Here, we show that NDRG2 acts to prevent cAMP and ,-catenin-mediated activation of the Mitf promoter, thereby blocking melanogenesis via the downstream Mitf target genes Tyrosinase, Tyrp1 and Dct. The data suggest that NDRG2 impairs melanogenesis by interfering with both the TCF/,-catenin and cAMP/CREB pathways that are known to stimulate Mitf expression in melanocytes and have major implications for the role of NDRG2 in pigmentation and melanoma progression. Taken together, the results not only identify NDRG2 as a novel regulator of pigmentation, but also potentially a key factor in regulating melanoma progression via Mitf. [source] NDRG2, a novel regulator of myoblast proliferation, is regulated by anabolic and catabolic factorsTHE JOURNAL OF PHYSIOLOGY, Issue 7 2009Victoria C. Foletta Skeletal muscle tissue undergoes adaptive changes in response to stress and the genes that control these processes are incompletely characterised. NDRG2 (N-myc downstream-regulated gene 2), a stress- and growth-related gene, was investigated in skeletal muscle growth and adaption. While NDRG2 expression levels were found to be up-regulated in both differentiated human and mouse myotubes compared with undifferentiated myoblasts, the suppression of NDRG2 in C2C12 myoblasts resulted in slowed myoblast proliferation. The increased expression levels of the cell cycle inhibitors, p21 Waf1/Cip1 and p27 Kip1, and of various muscle differentiation markers in NDRG2-deficient myoblasts indicate that a lack of NDRG2 promoted cell cycle exiting and the onset of myogenesis. Furthermore, the analysis of NDRG2 regulation in C2C12 myotubes treated with catabolic and anabolic agents and in skeletal muscle from human subjects following resistance exercise training revealed NDRG2 gene expression to be down-regulated during hypertrophic conditions, and conversely, up-regulated during muscle atrophy. Together, these data demonstrate that NDRG2 expression is highly responsive to different stress conditions in skeletal muscle and suggest that the level of NDRG2 expression may be critical to myoblast growth and differentiation. [source] The 14-3-3 protein as a novel regulator of ion channel localisationTHE JOURNAL OF PHYSIOLOGY, Issue 1 2002Masaru Ishii No abstract is available for this article. [source] Identification of AtHD2C as a novel regulator of abscisic acid responses in ArabidopsisTHE PLANT JOURNAL, Issue 1 2006Sunandini Sridha Summary HD2 proteins are plant-specific histone deacetylases. Little is known about the function of HD2 proteins in plants. In this paper, we report that an Arabidopsis HD2 protein, AtHD2C, is involved in abscisic acid and abiotic stress responses. Analysis of Arabidopsis plants containing the AtHD2C:, - glucuronidase fusion gene revealed that AtHD2C was constitutive expressed in plants. Furthermore, expression of AtHD2C was repressed by abscisic acid. Over-expression of 35S:AtHD2C-GFP in transgenic Arabidopsis plants conferred an abscisic acid-insensitive phenotype. In addition, 35S:AtHD2C-GFP transgenic plants displayed reduced transpiration and enhanced tolerance to salt and drought stresses when compared with wild-type plants. The expression of several abscisic acid-responsive genes was affected in the 35S:AtHD2C-GFP plants. Our study provides evidence indicating that AtHD2C can modulate abscisic acid and stress responses. [source] The VERNALIZATION INDEPENDENCE 4 gene encodes a novel regulator of FLOWERING LOCUS CTHE PLANT JOURNAL, Issue 5 2002Hua Zhang Summary The late-flowering, vernalization-responsive habit of many Arabidopsis ecotypes is mediated predominantly through repression of the floral programme by the FLOWERING LOCUS C (FLC) gene. To better understand this repressive mechanism, we have taken a genetic approach to identify novel genes that positively regulate FLC expression. We identified recessive mutations in a gene designated VERNALIZATION INDEPENDENCE 4 (VIP4), that confer early flowering and loss of FLC expression in the absence of cold. We cloned the VIP4 gene and found that it encodes a highly hydrophilic protein with similarity to proteins from yeasts, Drosophila, and Caenorhabditis elegans. Consistent with a proposed role as a direct activator of FLC, VIP4 is expressed throughout the plant in a pattern similar to that of FLC. However, unlike FLC, VIP4 RNA expression is not down-regulated in vernalized plants, suggesting that VIP4 is probably not sufficient to activate FLC, and that VIP4 is probably not directly involved in a vernalization mechanism. Epistasis analysis suggests that VIP4 could act in a separate pathway from previously identified FLC regulators, including FRIGIDA and the autonomous flowering promotion pathway gene LUMINIDEPENDENS. Mutants lacking detectable VIP4 expression flower earlier than FLC null mutants, suggesting that VIP4 regulates flowering-time genes in addition to FLC. Floral morphology is also disrupted in vip4 mutants; thus, VIP4 has multiple roles in development. [source] Hydrophobic peptides: novel regulators within bacterial membraneMOLECULAR MICROBIOLOGY, Issue 1 2009Eric Alix Summary Identification of short coding sequences is challenging, both experimentally and in silico, and functional natural peptides (< 50 amino acids) have to a large extent been overlooked in Gram-negative bacteria. Recent results have converged to highlight the role of hydrophobic peptides that form a novel class of active molecules in Escherichia coli and Salmonella enterica serovar Typhimurium. These peptides can play a regulatory role by interacting with protein partners at the inner membrane and by modulating protein partner activity or stability. Genome-wide analyses in both bacterial species have identified several conserved short open reading frames encoding a single transmembrane segment. We discuss the known and predicted membrane-associated peptides and the tools for their identification. Besides the identification of novel regulatory networks, characterization of peptides with a single transmembrane helix segment and proteins that interact with them provides a powerful opportunity to study interactions between alpha helices within biological membranes. In addition, some bioactive membrane peptides could provide a basis for engineering membrane protein antagonists. [source] TUSC4/NPRL2, a novel PDK1-interacting protein, inhibits PDK1 tyrosine phosphorylation and its downstream signalingCANCER SCIENCE, Issue 9 2008Atsuo Kurata 3-Phosphoinositide,dependent protein kinase-1 (PDK1) is a key regulator of cell proliferation and survival signal transduction. PDK1 is known to be constitutively active and is further activated by Src-mediated phosphorylation at the tyrosine-9, -373, and -376 residues. To identify novel regulators of PDK1, we performed E. coli -based two-hybrid screening and revealed that tumor suppressor candidate 4 (TUSC4), also known as nitrogen permease regulator-like 2 (NPRL2), formed a complex with PDK1 and suppressed Src-dependent tyrosine phosphorylation and activation of PDK1 in vitro and in cells. The NH2 -terminal 133 amino acid residues of TUSC4 were involved in binding to PDK1. The deletion mutant of TUSC4 that lacked the NH2 -terminal domain showed no inhibitory effects on PDK1 tyrosine phosphorylation or activation. Thus, complex formation is indispensable for TUSC4-mediated PDK1 inactivation. The siRNA-mediated down-regulation of TUSC4 induced cell proliferation, while ectopic TUSC4 expression inactivated the PDK1 downstream signaling pathway, including Akt and p70 ribosomal protein S6 kinase, and increased cancer cell sensitivity to several anticancer drugs. Our results suggest that TUSC4/NPRL2, a novel PDK1-interacting protein, plays a role in regulating the Src/PDK1 signaling pathway and cell sensitivity to multiple cancer chemotherapeutic drugs. (Cancer Sci 2008; 99: 1827,1834) [source] MicroRNAs: novel regulators in skin inflammationCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 3 2008E. Sonkoly Summary Compelling evidence indicates that microRNAs (miRNAs), short, non-protein coding RNAs, are critical for the development and survival of multicellular organisms. Recently, miRNAs were implicated in the pathogenesis of psoriasis and atopic eczema (AE), the two most common chronic inflammatory disorders in skin. In particular, miR-203, the first skin-specific miRNA, showing an intriguing expression profile being confined to skin epithelium, is specifically overexpressed in psoriasis. MiR-146a, another miRNA showing specific upregulation in psoriasis, is involved in the regulation of innate immune responses and the tumour necrosis factor (TNF)-, pathway. Interestingly, miR-125b, another miRNA involved in the TNF-, pathway, is also deregulated in psoriasis and AE. As skin inflammation may serve as a model for chronic inflammatory disorders, it is likely that miRNAs involved in skin inflammation will eventually emerge in other inflammatory or autoimmune disorders, and some of these may become disease markers and therapeutic targets. In this review we present an overview of what is currently known about the roles of miRNAs in chronic inflammatory skin disorders. [source] | |||||||||||||