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Master Regulator (master + regulator)
Selected AbstractsNF-,B in Photodynamic Therapy: Discrepancies of a Master RegulatorPHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 5 2006Jean-Yves Matroule ABSTRACT Tumor eradication by photodynamic therapy (PDT) results from the onset of distinct killing processes. In addition to the well-known necrotic and apoptotic mechanisms, PDT initiates an inflammatory response that will indirectly contribute to tumor clearance. The NF-,B transcription factor is a major regulator of inflammation modulating the expression of cyto-kines, chemokines, and adhesion molecules in various cell types in response to a large number of stimuli. Besides, NF-,B regulates the expression of antiapoptotic genes, cyclooxygenases (COXs) and metalloproteinases (MMPs) as well, thereby favoring tumor cell proliferation and dissemination. In the present review, we aim to summarize the current knowledge on NF-,B status following photosensitization of cancer cells and endothelial cells. In order to unravel the NF-,B impact in PDT tumorigenicity and recurrences, we will stress the discrepancies of this major transcription factor relative to the signaling cascades underlying its activation and the cellular effects triggered by its translocation into the nucleus and its binding to its target genes. [source] MicroRNAs: Master Regulators of Ethanol Abuse and Toxicity?ALCOHOLISM, Issue 4 2010Rajesh C. Miranda Ethanol exerts complex effects on human physiology and health. Ethanol is not only addictive, but it is also a fetal teratogen, an adult neurotoxin, and an etiologic agent in hepatic and cardiovascular disease, inflammation, bone loss, and fracture susceptibility. A large number of genes and signaling mechanisms have been implicated in ethanol's deleterious effects leading to the suggestion that ethanol is a "dirty drug." An important question is, are there cellular "master-switches" that can explain these pleiotropic effects of ethanol? MicroRNAs (miRNAs) have been recently identified as master regulators of the cellular transcriptome and proteome. miRNAs play an increasingly appreciated and crucial role in shaping the differentiation and function of tissues and organs in both health and disease. This critical review discusses new evidence showing that ethanol-sensitive miRNAs are indeed regulatory master-switches. More specifically, miRNAs control the development of tolerance, a crucial component of ethanol addiction. Other drugs of abuse also target some ethanol-sensitive miRNAs suggesting that common biochemical mechanisms underlie addiction. This review also discusses evidence that miRNAs mediate several ethanol pathologies, including disruption of neural stem cell proliferation and differentiation in the exposed fetus, gut leakiness that contributes to endotoxemia and alcoholic liver disease, and possibly also hepatocellular carcinomas and other gastrointestinal cancers. Finally, this review provides a perspective on emerging investigations into potential roles of miRNAs as mediators of ethanol's effects on inflammation and fracture healing, as well as the potential for miRNAs as diagnostic biomarkers and as targets for therapeutic interventions for alcohol-related disorders. [source] The zebrafish bHLH PAS transcriptional regulator, single-minded 1 (sim1), is required for isotocin cell developmentDEVELOPMENTAL DYNAMICS, Issue 8 2006Jennifer L. Eaton Abstract A wide range of physiological and behavioral processes, such as social, sexual, and maternal behaviors, learning and memory, and osmotic homeostasis are influenced by the neurohypophysial peptides oxytocin and vasopressin. Disruptions of these hormone systems have been linked to several neurobehavioral disorders, including autism, Prader-Willi syndrome, affective disorders, and obsessive-compulsive disorder. Studies in zebrafish promise to reveal the complex network of regulatory genes and signaling pathways that direct the development of oxytocin- and vasopressin-like neurons, and provide insight into factors involved in brain disorders associated with disruption of these systems. Isotocin, which is homologous to oxytocin, is expressed early, in a simple pattern in the developing zebrafish brain. Single-minded 1 (sim1), a member of the bHLH-PAS family of transcriptional regulatory genes, is required for terminal differentiation of mammalian oxytocin cells and is a master regulator of neurogenesis in Drosophila. Here we show that sim1 is expressed in the zebrafish forebrain and is required for isotocin cell development. The expression pattern of sim1 mRNA in the embryonic forebrain is dynamic and complex, and overlaps with isotocin expression in the preoptic area. We provide evidence that the role of sim1 in zebrafish neuroendocrine cell development is evolutionarily conserved with that of mammals. Developmental Dynamics 235:2071,2082, 2006. © 2006 Wiley-Liss, Inc. [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] The IFN regulatory factor 7-dependent type I IFN response is not essential for early resistance against murine cytomegalovirus infectionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2009Christian Steinberg Abstract IFN regulatory factor 7 (IRF7) has been described as the master regulator of type I IFN responses and has been shown to be critical for innate antiviral immunity in vivo. In addition to type I IFN, NK cell responses are involved in the control of viral replication during acute viral infection. To investigate the role of IRF7 in the context of a viral infection that induces a strong NK cell response, the murine cytomegalovirus (MCMV) infection model was used. WT, IRF7-deficient and IRF3/IRF7-double deficient mice were infected with MCMV. The systemic IFN-, response to MCMV was entirely dependent on IRF7, but independent of IRF3. However, peak IFN-, production during MCMV infection was not affected by the lack of IRF7 or both IRF7 and IRF3. Despite the complete lack of IFN-, production IRF7- and IRF3/IRF7-deficient mice were surprisingly efficient in controlling MCMV replication and were only modestly more susceptible to MCMV infection than WT mice. NK cell cytotoxicity was unimpaired and NK cell IFN-, production was enhanced in IRF7-deficient mice correlating with increased levels of bioactive IL-12. Owing to these compensatory mechanisms IRF7-dependent antiviral immune responses were not essential for resistance against acute MCMV infection in vivo. [source] Pathologic expression of MHC class,II is driven by mitogen-activated protein kinasesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2007Isabelle Martins Abstract The class,II transactivator (CIITA) is the master regulator of MHC class,II molecules (MHC,II). In melanoma, the MHC,II are constitutively expressed due to an abnormal transcription of CIITA from its promoter,III (pIII), and requires the presence of a 1-kb enhancer located upstream from this latter. Since mitogen-activated protein kinases (MAPK) have been shown to be activated in most melanomas, we sought to analyze their possible involvement in CIITA expression. Using chemical inhibitors and dominant-negative constructs of MAPK-ERK kinase (Mek1) and MAPK-JNK, we evidenced the inhibition of MHC,II and CIITA expression in melanoma cell lines displaying activated MAPK. Transcriptional regulation by MAPK is known to involve the AP-1 transcription factor family. Sequence analysis revealed an AP-1-responsive motif in the enhancer of CIITA pIII at ,5954/,5947 from the site of transcription initiation. Its mutagenesis reduced CIITA expression four- to fivefold in melanoma cell lines and alleviated the effect of dominant-negative constructs of the MAPK pathway. Together, our findings demonstrate that MAPK-ERK and MAPK-JNK are regulators of CIITA transcription in melanoma, and pinpoint an AP-1-responsive site in the CIITA gene pIII. This should have considerable impact on our understanding of the physio-pathologic expression of MHC,II. [source] Hypoxia-inducible factor as a physiological regulatorEXPERIMENTAL PHYSIOLOGY, Issue 6 2005Patrick H. Maxwell Hypoxia-inducible factor (HIF) is a transcription complex which responds to changes in oxygen, providing cells with a master regulator that coordinates changes in gene transcription. HIF operates in all mammalian cell types and is ancient in evolutionary terms, being conserved in C. elegans and D. melanogaster. This review summarizes recent insights into the molecular events that link reduced oxygenation to HIF activation and emerging insights into the extensive role of HIF in a broad range of physiological processes. [source] Complex phenotypes of a mutant inactivated for CymR, the global regulator of cysteine metabolism in Bacillus subtilisFEMS MICROBIOLOGY LETTERS, Issue 2 2010Marie-Françoise Hullo Abstract We characterized various phenotypes of a mutant inactivated for CymR, the master regulator of cysteine metabolism in Bacillus subtilis. The deletion of cymR resulted in impaired growth in the presence of cystine and increased sensitivity to hydrogen peroxide-, disulfide-, paraquat- and tellurite-induced stresses. Estimation of metabolite pools suggested that these phenotypes could be the result of profound metabolic changes in the ,cymR mutant including an increase of the intracellular cysteine pool and hydrogen sulfide formation, as well as a depletion of branched-chain amino acids. [source] Nitric oxide reduces astrocytic lactate production and induces neuronal vulnerability in stroke-prone spontaneously hypertensive ratsGLIA, Issue 4 2008Kazuo Yamagata Abstract Nitric oxide (NO) leads to neuronal death in ischemia/reperfusion (I/R), including stroke. Here, we examined the NO-induced vulnerability of neurons and lactate production by astrocytes in stroke-prone spontaneously hypertensive rats (SHRSP) in vitro. Neuronal cell death induced by the NO donor sodium nitroprusside (SNP) was significantly increased in SHRSP compared with Wistar kyoto rats (WKY). Furthermore, levels of lactate production by astrocytes were significantly reduced in SHRSP compared with WKY. At the same time, expressions of the lactate dehydrogenase (LDH) and monocarboxylate transporter 1 (MCT1) genes were significantly decreased by SNP in SHRSP compared with WKY. Moreover, in astrocytes isolated from SHRSP, the gene expression of isoforms of 6-phosphofracto-2-kinase (PFK2), a master regulator of glycolysis, namely PFK2.1, PFK2.2, PFK2.3, and PFK2.4, had deteriorated significantly. Notably, the SNP-evoked gene expression of PFK2.4 was lower in astrocytes of SHRSP than those of WKY. These results indicated that the neurons and astrocytes of SHRSP differed in responsiveness to SNP from those of WKY. This difference might explain the deficiency of energy and vulnerability to SNP of the neurons of SHRSP. © 2008 Wiley-Liss, Inc. [source] Subnuclear targeting of Runx1 Is required for synergistic activation of the myeloid specific M-CSF receptor promoter by PU.1,JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2005Xiangen Li Abstract Many types of acute myelogenous leukemia involve chromosomal translocations that target the C-terminus of Runx1/AML1 transcription factor, a master regulator of hematopoiesis. The C-terminus of Runx1/AML1 that includes the nuclear matrix targeting signal (NMTS) is essential for embryonic development, hematopoiesis, and target gene regulation. During the onset and normal progression of hematopoiesis, several lineage-specific factors such as C/EBP, and PU.1 interact with Runx1 to regulate transcription combinatorially. Here we addressed the functional interplay between subnuclear targeting of Runx1 and gene activation during hematopoiesis. Point mutations were generated in the NMTS of the human Runx1 protein and tested for their effect on transcriptional cooperativity with C/EBP, and PU.1 at myeloid-specific promoters. We characterized five mutants that do not alter nuclear import, DNA binding or C/EBP,-dependent synergistic activation of the target gene promoters. However a critical tyrosine in the NMTS is required for subnuclear targeting and activation of the granulocyte-macrophage colony stimulating factor (GM-CSF) promoter. Furthermore, this point mutation is defective for transcriptional synergism with PU.1 on the macrophage colony stimulating factor (MCSF) receptor c-FMS promoter. Our results indicate that the NMTS region of Runx1 is required for functional interactions with PU.1. Taken together, our findings establish that subnuclear targeting of Runx1 is a critical component of myeloid-specific transcriptional control. © 2005 Wiley-Liss, Inc. [source] Three independent signalling pathways repress motility in Pseudomonas fluorescens F113MICROBIAL BIOTECHNOLOGY, Issue 4 2009Ana Navazo Summary Motility is one of the most important traits for rhizosphere colonization by pseudomonads. Despite this importance, motility is severely repressed in the rhizosphere-colonizing strain Pseudomonas fluorescens F113. This bacterium is unable to swarm under laboratory conditions and produce relatively small swimming haloes. However, phenotypic variants with the ability to swarm and producing swimming haloes up to 300% larger than the wild-type strain, arise during rhizosphere colonization. These variants harbour mutations in the genes encoding the GacA/GacS two-component system and in other genes. In order to identify genes and pathways implicated in motility repression, we have used generalized mutagenesis with transposons. Analysis of the mutants has shown that besides the Gac system, the Wsp system and the sadB gene, which have been previously implicated in cyclic di-GMP turnover, are implicated in motility repression: mutants in the gacS, sadB or wspR genes can swarm and produce swimming haloes larger than the wild-type strain. Epistasis analysis has shown that the pathways defined by each of these genes are independent, because double and triple mutants show an additive phenotype. Furthermore, GacS, SadB and WspR act at different levels. Expression of the fleQ gene, encoding the master regulator of flagella synthesis is higher in the gacS - and sadB - backgrounds than in the wild-type strain and this differential expression is reflected by a higher secretion of the flagellin protein FliC. Conversely, no differences in fleQ expression or FliC secretion were observed between the wild-type strain and the wspR - mutant. [source] Regulation of AmtR-controlled gene expression in Corynebacterium glutamicum: mechanism and characterization of the AmtR regulonMOLECULAR MICROBIOLOGY, Issue 2 2005Gabriele Beckers Summary AmtR, the master regulator of nitrogen control in Corynebacterium glutamicum, represses transcription of a number of genes during nitrogen surplus. Repression is released by an interaction of AmtR with signal transduction protein GlnK. As shown by pull-down assays and gel retardation experiments, only adenylylated GlnK, which is present in the cells during nitrogen limitation, is able to bind to AmtR. The AmtR regulon was characterized in this study by a combination of bioinformatics, transcriptome and proteome analyses. At least 33 genes are directly controlled by the repressor protein including those encoding transporters and enzymes for ammonium assimilation (amtA, amtB, glnA, gltBD), urea and creatinine metabolism (urtABCDE, ureABCEFGD, crnT, codA), a number of biochemically uncharacterized enzymes and transport systems (NCgl1099, NCgl1100, NCgl 1915,1918) as well as signal transduction proteins (glnD, glnK). For the AmtR regulon, an AmtR box has been defined which comprises the sequence tttCTATN6AtAGat/aA. Furthermore, the transcriptional organization of AmtR-regulated genes and operons was characterized. [source] Quantitative analysis of the secretome of TGF-, signaling-deficient mammary fibroblastsPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 13 2010Baogang J. Xu Abstract Transforming growth factor , (TGF-,) is a master regulator of autocrine and paracrine signaling pathways between a tumor and its microenvironment. Decreased expression of TGF-, type II receptor (T,RII) in stromal cells is associated with increased tumor metastasis and shorter patient survival. In this study, SILAC quantitative proteomics was used to identify differentially externalized proteins in the conditioned media from the mammary fibroblasts with or without intact T,RII. Over 1000 proteins were identified and their relative differential levels were quantified. Immunoassays were used to further validate identification and quantification of the proteomic results. Differential expression was detected for various extracellular proteins, including proteases and their inhibitors, growth factors, cytokines, and extracellular matrix proteins. CXCL10, a cytokine found to be up-regulated in the T,RII knockout mammary fibroblasts, is shown to directly stimulate breast tumor cell proliferation and migration. Overall, this study revealed hundreds of specific extracellular protein changes modulated by deletion of T,RII in mammary fibroblasts, which may play important roles in the tumor microenvironment. These results warrant further investigation into the effects of inhibiting the TGF-, signaling pathway in fibroblasts because systemic inhibition of TGF-, signaling pathways is being considered as a potential cancer therapy. [source] ELL is an HIF-1, partner that regulates and responds to hypoxia response in PC3 cellsTHE PROSTATE, Issue 7 2010Lingqi Liu Abstract BACKGROUND Eleven,nineteen lysine-rich leukemia (ELL) plays an important role in tumorigenesis and animal development. HIF-1 is a transcriptional factor that functions as a master regulator of O2 homeostasis. Our previous studies showed that a binding partner of ELL, U19/Eaf2, can modulate HIF-1, activity and hypoxia response, suggesting that ELL may also influence HIF-1, pathway and hypoxia response. METHODS Co-localization and co-immunoprecipitation were performed to test the interaction between ELL and HIF-1,. PC3 cells with stable ELL knockdown and PC3 cells with stable ELL overexpression, along with their controls, were established using lentiviral expression system. Western blot and real-time PCR were performed to test the effect of ELL on HIF-1, protein and its down-stream gene transcription. To elucidate potential effect of hypoxia on ELL, cell growth and colony formation assays were performed using PC3 subline with stable ELL overexpression. RESULTS ELL is associated with HIF-1, in transfected cells. In PC3 prostate cancer cells, ELL inhibited HIF-1, protein level and down-stream gene expression. As expected, ELL inhibited cell growth and colony formation under normoxia. Interestingly, the inhibition was alleviated under hypoxia. CONCLUSIONS Our findings suggest that ELL and HIF-1, are binding partners and can modulate the functions of each other in hypoxia. Prostate 70: 797,805, 2010. © 2010 Wiley-Liss, Inc. [source] The homozygous P582S mutation in the oxygen-dependent degradation domain of HIF-1, is associated with increased risk for prostate cancerTHE PROSTATE, Issue 1 2007Avi Orr-Urtreger Abstract BACKGROUND The heterodimeric transcription factor HIF-1 (hypoxia-inducible factor 1), consisting of a critically regulated HIF-1, subunit and a constitutively expressed HIF-1, subunit, is a master regulator of genes involved in adaptation and survival under low-oxygen conditions. Increased levels of HIF-1 activity are associated with increased tumor aggressiveness, therapeutic resistance, and mortality. METHODS We studied 402 prostate cancer patients for the presence of the 1772C,>,T (P582S) and 1790G,>,A (A588T) mutations within the oxygen-dependent domain of HIF-1,. RESULTS Homozygosity for the P582S mutation was fourfold greater among prostate cancer patients compared to controls (OR,=,4.10 [C.I. 95% 1.11,<,OR,<,17.87], P,=,0.018). The existence of this mutation in prostate cancer patients was not associated with any of the clinical or pathological characteristics of the disease. No significant differences were found between the frequencies of A588T mutation in prostate cancer patients and controls. CONCLUSIONS Our data suggest that homozygous HIF1A P582S mutation confers significant susceptibility to prostate cancer. Prostate 67:8,13, 2007. © 2006 Wiley-Liss, Inc. [source] Red jungle fowl (Gallus gallus) as a model for studying the molecular mechanism of seasonal reproductionANIMAL SCIENCE JOURNAL, Issue 3 2009Hiroko ONO ABSTRACT Photoperiodism is an adaptation mechanism that enables animals to predict seasonal changes in the environment. Japanese quail is the best model organism for studying photoperiodism. Although the recent availability of chicken genome sequences has permitted the expansion from single gene to genome-wide transcriptional analysis in this organism, the photoperiodic response of the domestic chicken is less robust than that of the quail. Therefore, in the present study, we examined the photoperiodic response of the red jungle fowl (Gallus gallus), a predecessor of the domestic chicken, to test whether this animal could be developed as an ideal model for studying the molecular mechanisms of seasonal reproduction. When red jungle fowls were transferred from short-day- to long-day conditions, gonadal development and an increase in plasma LH concentration were observed. Furthermore, rapid induction of thyrotropin beta subunit, a master regulator of photoperiodism, was observed at 16 h after dawn on the first long day. In addition, the long-day condition induced the expression of type 2 deiodinase, the key output gene of photoperiodism. These results were consistent with the results obtained in quail and suggest that the red jungle fowl could be an ideal model animal for the genome-wide transcriptional analysis of photoperiodism. [source] Hypoxia-inducible factor-1, expression in experimental cirrhosis: correlation with vascular endothelial growth factor expression and angiogenesis,APMIS, Issue 7 2007SEVGI BOZOVA Angiogenesis progresses together with fibrogenesis during chronic liver injury. Hypoxia-inducible factor-1, (HIF-1,), a master regulator of homeostasis, plays a pivotal role in hypoxia-induced angiogenesis through its regulation of vascular endothelial growth factor (VEGF). The association between hypoxia, angiogenesis and VEGF expression has been demonstrated in experimental cirrhosis. However, expression of HIF-1, has yet to be reported. The aim of this study was to investigate the significance of HIF-1, expression during experimental liver fibrosis and the relationships between HIF-1, expression, VEGF expression and angiogenesis. Cirrhosis was induced in male Wistar rats by intraperitoneal administration of diethyl nitrosamine (DEN) (100 mg/kg, once a week). The serial sections from liver tissues were stained with anti-HIF-1,, anti-VEGF and anti-CD34 antibodies before being measured by light microscopy. Our results showed that HIF-1, expression gradually increases according to the severity of fibrosis (p<0.01). Moreover, its expression was found to be correlated with angiogenesis (r=0.916) and VEGF expression (r=0.969). The present study demonstrates that HIF-1, might have a role in the development of angiogenesis via regulation of VEGF during experimental liver fibrogenesis and suggests that this factor could be a potential target in the manipulation of angiogenesis in chronic inflammatory diseases of the liver. [source] Overexpression of interleukin-23, but not interleukin-17, as an immunologic signature of subclinical intestinal inflammation in ankylosing spondylitisARTHRITIS & RHEUMATISM, Issue 4 2009Francesco Ciccia Objective Subclinical gut inflammation is common in spondylarthritis, but the immunologic abnormalities underlying this process are undefined. Perturbation of the interleukin-23 (IL-23)/Th17 axis has emerged as a fundamental trigger of chronic inflammation. This study was undertaken to investigate the expression and tissue distribution of IL-23/Th17,related molecules in Crohn's disease (CD) and in subclinical gut inflammation in ankylosing spondylitis (AS). Methods Quantitative gene expression analysis of Th1/Th2 and IL-23/Th17 responses was performed in intestinal biopsy samples obtained from 12 patients with CD, 15 patients with AS, and 13 controls. IL-23 tissue distribution and identification of IL-23,producing cells were evaluated by immunohistochemistry. Results We demonstrated a strong and significant up-regulation of IL-23p19 transcripts in the terminal ileum in patients with AS and patients with CD. IL-23 was abundantly produced by infiltrating monocyte-like cells in inflamed mucosa from AS and CD patients. Notably, we also identified Paneth cells as a major source of IL-23 in patients with AS, patients with CD, and normal controls. Unlike CD, in AS patients, IL-23 was not associated with up-regulation of IL-17 and the IL-17,inducing cytokines IL-6 and IL-1,. Finally, while the Th1-related cytokines interferon-,, IL-12p35, and IL-27p28 were overexpressed only in CD patients, IL-4, IL-5, and STAT-6 were also significantly increased in AS patients. Conclusion Our findings indicate that overexpression of IL-23, but not IL-17, is a pivotal feature of subclinical gut inflammation in AS. Identification of resident Paneth cells as a pivotal source of IL-23 in physiologic and pathologic conditions strongly suggests that IL-23 is a master regulator of gut mucosal immunity, providing a pathophysiologic significance to the reported association between IL-23 receptor polymorphisms and intestinal inflammation. [source] The Wnt/,-catenin pathway: master regulator of liver zonation?BIOESSAYS, Issue 11 2006Zoë D. Burke The liver contains two systems for the removal of ammonia,the urea cycle and the enzyme glutamine synthetase. These systems are expressed in a complementary fashion in two distinct populations of hepatocytes, referred to as periportal and perivenous cells. One of the unresolved problems in hepatology has been to elucidate the molecular mechanisms responsible for induction and maintenance of the cellular heterogeneity for ammonia detoxification. There is now a potential molecular explanation for the zonation of the urea cycle and glutamine synthetase based on the Wnt/,-catenin pathway. BioEssays 28: 1072,1077, 2006. © 2006 Wiley Periodicals, Inc. [source] Mitochondrial biogenesis: Which part of "NO" do we understand?BIOESSAYS, Issue 6 2003Scot C. Leary A recent paper by Nisoli et al.1 provides the first evidence that elevated levels of nitric oxide (NO) stimulate mitochondrial biogenesis in a number of cell lines via a soluble guanylate-cyclase-dependent signaling pathway that activates PGC1, (peroxisome proliferator-activated receptor , coactivator-1,), a master regulator of mitochondrial content. These results raise intriguing possibilities for a role of NO in modulating mitochondrial content in response to physiological stimuli such as exercise or cold exposure. However, whether this signaling cascade represents a widespread mechanism by which mammalian tissues regulate mitochondrial content, and how it might integrate with other pathways that control PGC1, expression, remain unclear. BioEssays 25:538,541, 2003. © 2003 Wiley Periodicals, Inc. [source] Cycle-regulated genes and cell cycle regulationBIOESSAYS, Issue 7 2001Richard D'Ari The transcriptional profile of the entire Caulobacter crescentus genome over a synchronous cell cycle was recently described.(1) The analysis reveals a stunning 553 cell-cycle-regulated genes or orfs, nearly 19% of the genome, including putative functions in virtually all biological activities. Over a quarter of these genes/orfs respond to the Caulobacter master regulator, CtrA, most of them apparently indirectly. The analysis confirms and extends earlier observations showing that many proteins involved in cell cycle functions are expressed at the cell age when they are needed. Conversely, the data suggest that proteins specifically expressed at a particular age may be involved in a process taking place then. BioEssays 23:563,565, 2001. © 2001 John Wiley & Sons, Inc. [source] Emergence of protein kinase CK2 as a key target in cancer therapyBIOFACTORS, Issue 3 2010Janeen H. Trembley Abstract Protein kinase CK2, a protein serine/threonine kinase, plays a global role in activities related to cell growth, cell death, and cell survival. CK2 has a large number of potential substrates localized in diverse locations in the cell including, for example, NF-,B as an important downstream target of the kinase. In addition to its involvement in cell growth and proliferation it is also a potent suppressor of apoptosis, raising its key importance in cancer cell phenotype. CK2 interacts with diverse pathways which illustrates the breadth of its impact on the cellular machinery of both cell growth and cell death giving it the status of a "master regulator" in the cell. With respect to cancer, CK2 has been found to be dysregulated in all cancers examined demonstrating increased protein expression levels and nuclear localization in cancer cells compared with their normal counterparts. We originally proposed CK2 as a potentially important target for cancer therapy. Given the ubiquitous and essential for cell survival nature of the kinase, an important consideration would be to target it specifically in cancer cells while sparing normal cells. Towards that end, our design of a tenascin based sub-50 nm (i.e., less than 50 nm size) nanocapsule in which an anti-CK2 therapeutic agent can be packaged is highly promising because this formulation can specifically deliver the cargo intracellularly to the cancer cells in vivo. Thus, appropriate strategies to target CK2 especially by molecular approaches may lead to a highly feasible and effective approach to eradication of a given cancer. [source] The function of vascular endothelial growth factorBIOFACTORS, Issue 4 2009Bonnie J. Nieves Abstract Vascular endothelial growth factor (VEGF) is considered the master regulator of angiogenesis during growth and development, as well as in disease states such as cancer, diabetes, and macular degeneration. This review details our current understanding of VEGF signaling and discusses the benefits and unexpected side effects of promising anti-angiogenic therapeutics that are currently being used to inhibit neovacularization in tumors. © 2009 International Union of Biochemistry and Molecular Biology, Inc. [source] Strategy and mechanism for the prevention of hepatocellular carcinoma: Phosphorylated retinoid X receptor , is a critical target for hepatocellular carcinoma chemopreventionCANCER SCIENCE, Issue 3 2009Masahito Shimizu Hepatocellular carcinoma (HCC) is a major health care problem worldwide. The prognosis of patients with HCC is poor because even in the early stages when surgical treatment might be expected to be curative, the incidence of recurrence in patients with underlying cirrhosis is very high due to multicentric carcinogenesis. Therefore, strategies to prevent recurrence and second primary HCC are required to improve the prognosis. One of the most practical approaches to prevent the multicentric development of HCC is ,clonal deletion' therapy, which is defined as the removal of latent (i.e. invisible) (pre)malignant clones from the liver in a hypercarcinogenic state. Retinoids, a group of structural and functional analogs of vitamin A, exert their biological function primarily through two distinct nuclear receptors, retinoic acid receptors and retinoid X receptors (RXR), and abnormalities in the expression and function of these receptors are highly associated with the development of various cancers, including HCC. In particular, a malfunction of RXR, due to phosphorylation by the Ras,mitogen-activated protein kinase signaling pathway is profoundly associated with the development of HCC and thus may be a critical target for HCC chemoprevention. Acyclic retinoid, which has been clinically shown to reduce the incidence of a post-therapeutic recurrence of HCC, can inhibit Ras activity and phosphorylation of the extracellular signal-regulated kinase and RXR, proteins. In conclusion, the inhibition of RXR, phosphorylation and the restoration of its physiological function as a master regulator for nuclear receptors may be a potentially effective strategy for HCC chemoprevention and clonal deletion. Acyclic retinoid, which targets phosphorylated RXR,, may thus play a critical role in preventing the development of multicentric HCC. (Cancer Sci 2009; 100: 369,374) [source] Immunostimulatory Effects of Mesenchymal Stem Cell-Derived Neurons: Implications for Stem Cell Therapy in Allogeneic TransplantationsCLINICAL AND TRANSLATIONAL SCIENCE, Issue 1 2008Marianne D. Castillo Abstract Mesenchymal stem cells (MSCs) differentiate along various lineages to specialized mesodermal cells and also transdifferentiate into cells such as ectodermal neurons. MSCs are among the leading adult stem cells for application in regenerative medicine. Advantages include their immune-suppressive properties and reduced ethical concerns. MSCs also show immune-enhancing functions. Major histocompatibility complex II (MHC-II) is expected to be downregulated in MSCs during neurogenesis. Ideally, "off the shelf" MSCs would be suited for rapid delivery into patients. The question is whether these MSC-derived neurons can reexpress MHC-II in a milieu of inflammation. Western analyses demonstrated gradual decrease in MHC-II during neurogenesis, which correlated with the expression of nuclear CIITA, the master regulator of MHC-II expression. MHC-II expression was reversed by exogenous IFNY. One-way mixed lymphocyte reaction with partly differentiated neurons showed a stimulatory effect, which was partly explained by the release of the proinflammatory neurotransmitter substance P (SP), cytokines, and decreases in miR-130a and miR-206. The anti-inflammatory neurotransmitters VIP and CGRP were decreased at the peak time of immune stimulation. In summary, MSC-derived neurons show decreased MHC-II expression, which could be reexpressed by IFNY. The release of neurotransmitters could be involved in initiating inflammation, underscoring the relevance of immune responses as consideration for stem cell therapies. [source] Abnormal expression of PPAR gamma isoforms in the subcutaneous adipose tissue of patients with Cushing's diseaseCLINICAL ENDOCRINOLOGY, Issue 1 2007Fausto Bogazzi Summary Background, Obesity is a clinical feature of patients with Cushing's disease. Peroxisome proliferators-activated receptor (PPAR), is the master regulator of adipogenesis; however, the expression of PPAR, isoforms in the subcutaneous adipose tissue (SAT) of patients with Cushing's disease is unknown. Aim and methods, The expression of PPAR,1 and PPAR,2 was evaluated by real-time reverse transcription polymerase chain reaction (RT-PCR) and immunofluorescence (PPAR,2 only) in SAT samples of 7 patients with untreated active Cushing's disease (CushingUNTR), 8 with Cushing's disease in remission (CushingREM) after pituitary adenomectomy, 15 normal lean subjects (ControlLEAN), and 15 obese patients (ControlOBE). Results, ControlLEAN had a higher degree of PPAR,1 than PPAR,2 (PPAR,2/PPAR,1 ratio, 0·55 ± 0·35). PPAR,2/PPAR,1 ratio decreased in CushingUNTR (0·10 ± 0·043, P < 0·03 vs. ControlLEAN and ControlOBE), because of either increased PPAR,1 or reduced PPAR,2 expression. PPAR,2/PPAR,1 ratio was 0·48 ± 0·07 in CushingREM patients (P < 0·04 vs. CushingUNTR, P < 0·03 vs. ControlOBE). PPAR,2/PPAR,1 ratio was higher in ControlOBE 0·90 ± 0·38 than in ControlLEAN (P < 0·005 vs. ControlLEAN, P < 0·03 vs. CushingREM, P < 0·009 vs. CushingUNTR). PPAR,2/PPAR,1 ratio was related to serum cortisol levels only in patients with Cushing'disease (r = 0·688, P < 0·02). Conclusions, CushingUNTR patients had an abnormal expression of PPAR, isoforms in SAT related to serum cortisol levels. Although further studies are necessary, it is conceivable that variations in the expression of PPAR, isoforms might have a role in the abnormal adipogenesis of patients with Cushing's disease. [source] The key regulators of adult T helper cell responses, STAT6 and T-bet, are established in early life in miceEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2006Shawn Rose Abstract Murine neonatal immunity is typically Th2 biased. This is characterized by high-level IL-4 production at all phases of the immune response and poor IFN-, memory responses. The differential expression of Th1/Th2 cytokines by neonates and adults could arise if the critical regulators of Th differentiation and function, STAT6 and T-bet, operate differently during the neonatal period. To test this idea, the Th cell responses of wild-type, T-bet-deficient, or STAT6-deficient mice were compared in vitro and in vivo. The absence of these factors had similar qualitative effects on the development of effector function in neonates and adults, i.e., if a Th lineage was inhibited or enhanced in adult animals, a similar phenomenon was observed in neonates. However, there was a striking difference observed in the in vivo Th1 memory responses of STAT6-deficient mice initially immunized as neonates. Antigen-specific IFN-, production was increased 50,100-fold in STAT6-deficient neonates, achieving levels similar to those of STAT6-deficient adults. These findings demonstrate that STAT6 and T-bet signals are central in shaping Th responses in wild-type neonates, as in adult mice, and that the master regulators of Th cell development and function are already firmly established in early life. [source] Control of DNA replication licensing in a cell cycleGENES TO CELLS, Issue 6 2002Hideo Nishitani To maintain genome integrity in eukaryotes, DNA must be duplicated precisely once before cell division occurs. A process called replication licensing ensures that chromosomes are replicated only once per cell cycle. Its control has been uncovered by the discovery of the CDKs (cyclin dependent kinases) as master regulators of the cell cycle and the initiator proteins of DNA replication, such as the Origin Recognition Complex (ORC), Cdc6/18, Cdt1 and the MCM complex. At the end of mitosis, the MCM complex is loaded on to chromatin with the aid of ORC, Cdc6/18 and Cdt1, and chromatin becomes licensed for replication. CDKs, together with the Cdc7 kinase, trigger the initiation of replication, recruiting the DNA replicating enzymes on sites of replication. The activated MCM complex appears to play a key role in the DNA unwinding step, acting as a replicating helicase and moves along with the replication fork, at the same time bringing the origins to the unlicensed state. The cycling of CDK activity in the cell cycle separates the two states of replication origins, the licensed state in G1-phase and the unlicensed state for the rest of the cell cycle. Only when CDK drops at the completion of mitosis, is the restriction on licensing relieved and a new round of replication is allowed. Such a CDK-regulated licensing control is conserved from yeast to higher eukaryotes, and ensures that DNA replication takes place only once in a cycle. Xenopus laevis and mammalian cells have an additional system to control licensing. Geminin, whose degradation at the end of mitosis is essential for a new round of licensing, has been shown to bind Cdt1 and negatively regulate it, providing a new insight into the regulation of DNA replication in higher eukaryotes. [source] Identification of developmentally regulated expression of MuSK in astrocytes of the rodent retinaJOURNAL OF NEUROCHEMISTRY, Issue 2 2006Tatiana Cheusova Abstract One of the master regulators of postsynaptic neuromuscular synaptogenesis is the muscle-specific receptor tyrosine kinase (MuSK). In mammals prominent MuSK expression is believed to be restricted to skeletal muscle. Upon activation by nerve-derived agrin MuSK-dependent signalling participates in both the induction of genes encoding postsynaptic components and aggregation of nicotinic acetylcholine receptors (AChR) in the subsynaptic muscle membrane. Strikingly, expression of certain isoforms of nerve-derived agrin can also be detected in the CNS. In this study, we examined the expression of MuSK in the brain and eye of rodents. In the retina MuSK was expressed in astrocytes between postnatal days 7 and 14, i.e. at the time when the eyes open. We found that agrin was localized adjacent to MuSK-expressing astrocytes which in turn were detected close to the inner limiting membrane of the rodent retina. In summary, the presence of MuSK on retinal astrocytes suggests a novel role of MuSK signalling pathways in the CNS. [source] MicroRNAs: Master Regulators of Ethanol Abuse and Toxicity?ALCOHOLISM, Issue 4 2010Rajesh C. Miranda Ethanol exerts complex effects on human physiology and health. Ethanol is not only addictive, but it is also a fetal teratogen, an adult neurotoxin, and an etiologic agent in hepatic and cardiovascular disease, inflammation, bone loss, and fracture susceptibility. A large number of genes and signaling mechanisms have been implicated in ethanol's deleterious effects leading to the suggestion that ethanol is a "dirty drug." An important question is, are there cellular "master-switches" that can explain these pleiotropic effects of ethanol? MicroRNAs (miRNAs) have been recently identified as master regulators of the cellular transcriptome and proteome. miRNAs play an increasingly appreciated and crucial role in shaping the differentiation and function of tissues and organs in both health and disease. This critical review discusses new evidence showing that ethanol-sensitive miRNAs are indeed regulatory master-switches. More specifically, miRNAs control the development of tolerance, a crucial component of ethanol addiction. Other drugs of abuse also target some ethanol-sensitive miRNAs suggesting that common biochemical mechanisms underlie addiction. This review also discusses evidence that miRNAs mediate several ethanol pathologies, including disruption of neural stem cell proliferation and differentiation in the exposed fetus, gut leakiness that contributes to endotoxemia and alcoholic liver disease, and possibly also hepatocellular carcinomas and other gastrointestinal cancers. Finally, this review provides a perspective on emerging investigations into potential roles of miRNAs as mediators of ethanol's effects on inflammation and fracture healing, as well as the potential for miRNAs as diagnostic biomarkers and as targets for therapeutic interventions for alcohol-related disorders. [source] | |||||||||||||||||||||||||