Transcriptional Repression (transcriptional + repression)

Distribution by Scientific Domains
Distribution within Life Sciences


Selected Abstracts


A novel, promoter-based, target-specific assay identifies 2-deoxy- d -glucose as an inhibitor of globotriaosylceramide biosynthesis

FEBS JOURNAL, Issue 18 2009
Tetsuya Okuda
Abnormal biosynthesis of globotriaosylceramide (Gb3) is known to be associated with Gb3-related diseases, such as Fabry disease. The Gb3 synthase gene (Gb3S) codes for ,1,4-galactosyltransferase, which is a key enzyme involved in Gb3 biosynthesis in vivo. Transcriptional repression of Gb3S is a way to control Gb3 biosynthesis and may be a suitable target for the treatment of Gb3-related diseases. To find a transcriptional inhibitor for Gb3S, we developed a convenient cell-based chemical screening assay system by constructing a fusion gene construct of the human Gb3S promoter and a secreted luciferase as reporter. Using this assay, we identified 2-deoxy- d -glucose as a potent inhibitor for the Gb3S promoter. In cultured cells, 2-deoxy- d -glucose markedly reduced endogenous Gb3S mRNA levels, resulting in a reduction in cellular Gb3 content and a corresponding accumulation of the precursor lactosylceramide. Moreover, cytokine-induced expression of Gb3 on the cell surface of endothelial cells, which is closely related to the onset of hemolytic uremic syndrome in O157-infected patients, was also suppressed by 2-deoxy- d -glucose treatment. These results indicate that 2-deoxy- d -glucose can control Gb3 biosynthesis through the inhibition of Gb3S transcription. Furthermore, we demonstrated the general utility of our novel screening assay for the identification of new inhibitors of glycosphingolipid biosynthesis. [source]


Genetic basis of rett syndrome

DEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 2 2002
Ignatia B. Van den Veyver
Abstract The origin of Rett syndrome has long been debated, but several observations have suggested an X-linked dominant inheritance pattern. We and others have pursued an exclusion-mapping strategy using DNA from a small number of familial Rett syndrome cases. This work resulted in the narrowing of the region likely to harbor the mutated gene to Xq27.3-Xqter. After systematic exclusion of several candidate genes, we discovered mutations in MECP2, the gene that encodes the transcriptional repressor, methyl-CpG-binding protein 2. Since then, nonsense, missense, or frameshift mutations have been found in at least 80% of girls affected with classic Rett syndrome. Sixty-four percent of mutations are recurrent C > T transitions at eight CpG dinucleotides mutation hotspots, while the C-terminal region of the gene is prone to recurrent multinucleotide deletions (11%). Most mutations are predicted to result in total or partial loss of function of MeCP2. There is no clear correlation between the type and position of the mutation and the phenotypic features of classic and variant Rett syndrome patients, and XCI appears to be a major determinant of phenotypic severity. Further research focuses on the pathogenic consequences of these mutations along the hypothesis of loss of transcriptional repression of a small number of genes that are essential for neuronal function in the maturing brain. MRDD Research Reviews 2002;8:82,86. © 2002 Wiley-Liss, Inc. [source]


IL-10 modulates cytokine gene transcription by protein synthesis-independent and dependent mechanisms in lipopolysaccharide-treated neutrophils

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2007
Marzia Rossato
Abstract We have recently reported that the ability of IL-10 to rapidly exert its anti-inflammatory effects on human neutrophils is dependent upon exposure of these cells to LPS for at least 3,4,h. Here, we demonstrate that, in neutrophils "preconditioned" by LPS, IL-10 primarily targets the transcription of TNF-,, CXCL8 and IL-1ra genes, as revealed by primary transcript real-time RT-PCR. We also show that IL-10-induced transcriptional repression of TNF-, and CXCL8 genes consists of two distinct phases: an early one, occurring rapidly and in a protein synthesis-independent manner, followed by a second phase, more delayed and dependent on protein synthesis. Interestingly, the protein synthesis dependence of the latter phase coincides with a reduced ability of IL-10 to induce STAT3 tyrosine phosphorylation. Importantly, inhibition of IL-10-induced STAT3 activation and IL-10-suppressive action by a prolonged exposure to cycloheximide (CHX) was observed to occur also in human monocytes and was caused by a defective IL-10-mediated activation of Jak1 and Tyk2 kinases. Taken together, our findings suggest that CHX interferes with the IL-10-mediated intracellular signaling pathway by interrupting events upstream of STAT3 activation. These data question the concept of the requirement of an IL-10-induced mediator as the unique mechanism to execute IL-10 anti-inflammatory program. [source]


Nuclear repositioning marks the selective exclusion of lineage-inappropriate transcription factor loci during T helper cell differentiation

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2004
Susannah
Abstract To address how heritable patterns of gene expression are acquired during the differentiation of Th1 and Th2 cells, we analyzed the nuclear position of lineage-restricted cytokine genes and their upstream regulators by 3-dimensional fluorescence in situ hybridization. During Th1 differentiation, GATA-3 and c-maf loci, which encode upstream regulators of Th2 cytokines, were progressively repositioned to centromeric heterochromatin as defined by a ,-satellite repeat probe and/or the nuclear periphery, compartments that have been associated with transcriptional repression. A third transcription factor locus, T-bet, which controls Th1-specific programs, was subject to de novo CpG methylation in a Th2 cell clone. In contrast, we did not find repositioning of the cytokine gene loci IL-2, IL-3, IL-4 or IFN-, during T helper cell differentiation. Instead, IFN-, was constitutively associated with the nuclear periphery, even when primed for expression in Th1 cells. Our results suggest that Th1/Th2 lineage commitment and differentiation involve repositioning of the regulators of cytokine expression, rather than the cytokine genes themselves. [source]


Biological activity of RE-1 silencing transcription factor (REST) towards distinct transcriptional activators

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2001
Michael Lietz
Abstract The zinc finger protein RE-1 silencing transcription factor (REST) is a transcriptional repressor that represses neuronal genes in non-neuronal tissues. We have analyzed the ability of REST and the REST mutants, REST,N and REST,C lacking either the N-terminal or C-terminal repression domains of REST, to inhibit transcription mediated by distinct transcriptional activator proteins. For this purpose we have designed an activator specific assay where transcription is activated as a result of only one distinct activation domain. In addition, binding sites for REST were inserted in the 5,-untranslated region or at a distant position downstream of the polyadenylation signal. The results show that REST or the REST mutants containing only one repression domain were able to block transcriptional activation mediated by the transcriptional activation domains derived from p53, AP2, Egr-1, and GAL4. Moreover, REST, as well as the REST mutants, blocked the activity of the phosphorylation-dependent activation domain of Elk1. However, the activity of the activation domain derived from cAMP response element binding protein 2 (CREB2), was not inhibited by REST, REST,N or REST,C, suggesting that REST is able to distinguish between distinct transcriptional activation domains. Additionally, the activator specific assay, together with a positive-dominant mutant of REST that activated instead of repressed transcription, was used in titration experiments to show that REST has transcriptional repression and no transcriptional activation properties when bound to the 5,-untranslated region of a gene. [source]


Ski co-repressor complexes maintain the basal repressed state of the TGF-, target gene, SMAD7, via HDAC3 and PRMT5

GENES TO CELLS, Issue 1 2009
Takanori Tabata
The products encoded by ski and its related gene, sno, (Ski and Sno) act as transcriptional co-repressors and interact with other co-repressors such as N-CoR/SMRT and mSin3A. Ski and Sno mediate transcriptional repression by various repressors, including Mad, Rb and Gli3. Ski/Sno also suppress transcription induced by multiple activators, such as Smads and c-Myb. In particular, the inhibition of TGF-,-induced transcription by binding to Smads is correlated with the oncogenic activity of Ski and Sno. However, the molecular mechanism by which Ski and Sno mediate transcriptional repression remains unknown. In this study, we report the purification and characterization of Ski complexes. The Ski complexes purified from HeLa cells contained histone deacetylase 3 (HDAC3) and protein arginine methyltransferase 5 (PRMT5), in addition to multiple Smad proteins (Smad2, Smad3 and Smad4). Chromatin immunoprecipitation assays indicated that these components of the Ski complexes were localized on the SMAD7 gene promoter, which is the TGF-, target gene, in TGF-,-untreated HepG2 cells. Knockdown of these components using siRNA led to up-regulation of SMAD7 mRNA. These results indicate that Ski complexes serve to maintain a TGF-,-responsive promoter at a repressed basal level via the activities of histone deacetylase and histone arginine methyltransferase. [source]


Ebp2p, yeast homologue of a human protein that interacts with Epstein,Barr virus Nuclear Antigen 1, is required for pre-rRNA processing and ribosomal subunit assembly

GENES TO CELLS, Issue 7 2000
Rota Tsujii
Background A defect in the secretory pathway causes the transcriptional repression of both rRNA and ribosomal protein genes in Saccharomyces cerevisiae, suggesting a coupling of ribosome synthesis and plasma membrane synthesis. Rrs1p, an essential nuclear protein, is required for the secretory response. Results EBP2, encoding the yeast homologue of a human protein that interacts with Epstein,Barr virus Nuclear Antigen 1, was cloned in a two-hybrid screen using RRS1 as a bait. The rrs1-1 mutation, which produces Rrs1p without the C-terminal half and causes a defect in the secretory response, almost abolished the interaction with Ebp2p. Ebp2p is essential for growth and is mainly localized in the nucleolus. The effects of Ebp2p depletion on ribosome biogenesis is quite similar to that of Rrs1p depletion; in the Ebp2p-depleted cells, the rate of pre-rRNA processing is slower, and significantly less mature 25S rRNA is produced compared to those in wild-type cells. The polysome pattern indicates that Ebp2p-depletion causes a decrease of 80S monosomes and polysomes, an accumulation of 40S subunits, and the appearance of half-mer polysomes. Conclusions Ebp2p is required for the maturation of 25S rRNA and 60S subunit assembly. Ebp2p may be one of the target proteins of Rrs1p for executing the signal to regulate ribosome biogenesis. [source]


Fenofibrate differentially regulates plasminogen activator inhibitor-1 gene expression via adenosine monophosphate,activated protein kinase,dependent induction of orphan nuclear receptor small heterodimer partner,

HEPATOLOGY, Issue 3 2009
Dipanjan Chanda
Plasminogen activator inhibitor type I (PAI-1) is a marker of the fibrinolytic system and serves as a possible predictor for hepatic metabolic syndromes. Fenofibrate, a peroxisome proliferator-activated receptor , (PPAR,) agonist, is a drug used for treatment of hyperlipidemia. Orphan nuclear receptor small heterodimer partner (SHP) plays a key role in transcriptional repression of crucial genes involved in various metabolic pathways. In this study, we show that fenofibrate increased SHP gene expression in cultured liver cells and in the normal and diabetic mouse liver by activating the adenosine monophosphate,activated protein kinase (AMPK) signaling pathway in a PPAR,-independent manner. Administration of transforming growth factor beta (TGF-,) or a methionine-deficient and choline-deficient (MCD) diet to induce the progressive fibrosing steatohepatitis model in C57BL/6 mice was significantly reversed by fenofibrate via AMPK-mediated induction of SHP gene expression with a dramatic decrease in PAI-1 messenger RNA (mRNA) and protein expression along with other fibrotic marker genes. No reversal was observed in SHP null mice treated with fenofibrate. Treatment with another PPAR, agonist, WY14643, showed contrasting effects on these marker gene expressions in wild-type and SHP null mice, demonstrating the specificity of fenofibrate in activating AMPK signaling. Fenofibrate exhibited a differential inhibitory pattern on PAI-1 gene expression depending on the transcription factors inhibited by SHP. Conclusion: By demonstrating that a PPAR,-independent fenofibrate-AMPK-SHP regulatory cascade can play a key role in PAI-1 gene down-regulation and reversal of fibrosis, our study suggests that various AMPK activators regulating SHP might provide a novel pharmacologic option in ameliorating hepatic metabolic syndromes. (HEPATOLOGY 2009.) [source]


Ectodomain shedding of membrane-anchored heparin-binding EGF like growth factor and subcellular localization of the C-terminal fragment in the cell cycle

JOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2005
Fujio Toki
Heparin-binding EGF-like growth factor (HB-EGF) is initially synthesized as a type I transmembrane protein (proHB-EGF). The proHB-EGF is shed by specific metalloproteases, releasing the N-terminal fragment into the extracellular space as a soluble growth factor (HB-EGF) and the C-terminal fragment (HB-EGF-C) into the intracellular space, where it prevents transcriptional repression by the promyelocytic leukemia zinc finger protein (PLZF). The goal of the present study was to characterize regulation of proHB-EGF shedding and study its temporal variations in HB-EGF-C localization throughout the cell cycle. Quantitative combination analyses of cell surface proHB-EGF and HB-EGF in conditioned medium showed that proHB-EGF shedding occurred during the G1 cell cycle phase. Laser scanning cytometry (LSC) revealed that HB-EGF-C was internalized into the cytoplasm during the late G1 phase and accumulated in the nucleus beginning in the S phase. Subsequent nuclear export of PLZF occurred during the late S phase. Further, HB-EGF-C was localized around the centrosome following breakdown of the nuclear envelope and was localized to the interzonal space with chromosome segregation in the late M phase. Temporal variations in HB-EGF localization throughout the cell cycle were also characterized by time-lapse imaging of cells expressing YFP-tagged proHB-EGF, and these results were consistent with those obtained in cytometry studies. These results indicate that proHB-EGF shedding and subsequent HB-EGF-C signaling are related with progression of the cell cycle and may provide a clue to understand the unique biological significance of non-receptor-mediated signaling of proHB-EGF in cell growth. © 2004 Wiley-Liss, Inc. [source]


Loss of functional transforming growth factor (TGF)-, type II receptor results in insensitivity to TGF-,1-mediated apoptosis and Epstein,Barr virus reactivation

JOURNAL OF MEDICAL VIROLOGY, Issue 11 2006
Makoto Fukuda
Abstract Transforming growth factor (TGF)-,1 induces not only cell growth inhibition or apoptosis but also Epstein,Barr virus (EBV) reactivation in some Burkitt's lymphoma (BL) cell lines. The purpose of this study was to define the role of TGF-, signaling molecules in response to TGF-,1-mediated cell growth inhibition, apoptosis, and EBV reactivation in BL cell lines. First, we confirmed the effect of TGF-,1 on the cell growth and EBV reactivation in six BL cell lines. TGF-,1 induced cell growth inhibition and EBV reactivation in these cell lines but did not in Akata cells. To elucidate the mechanism of TGF-,1 unresponsiveness in Akata cells, we studied the expression of TGF-, receptors and the intracellular signaling molecules Smads. All cell lines expressed TGF-, type I receptor, Smad2, Smad3, and Smad4. TGF-, type II receptor (R-II) was expressed in all cell lines except Akata cells. Introduction of the TGF-, R-II into Akata cells results in sensitivity to TGF-,1-mediated growth inhibition, apoptosis, and EBV reactivation. In addition, to test a possibility to the transcriptional repression of the TGF-, R-II gene in Akata cells, the effect of histone deacetylation (HDAC) inhibitor, trichostatin A (TSA) was examined. The expression of TGF-, R-II in Akata cells was induced by TSA treatment. These results suggest that the lack of functional TGF-, R-II impedes the progression of signals through TGF-,1 and becomes a determinant of unresponsiveness to TGF-,1-mediated growth inhibition and EBV reactivation. J. Med. Virol. 78:1456,1464, 2006. © 2006 Wiley-Liss, Inc. [source]


Transcriptional activation of human mu-opioid receptor gene by insulin-like growth factor-I in neuronal cells is modulated by the transcription factor REST

JOURNAL OF NEUROCHEMISTRY, Issue 6 2008
Andrea Bedini
Abstract The human mu-opioid receptor gene (OPRM1) promoter contains a DNA sequence binding the repressor element 1 silencing transcription factor (REST) that is implicated in transcriptional repression. We investigated whether insulin-like growth factor I (IGF-I), which affects various aspects of neuronal induction and maturation, regulates OPRM1 transcription in neuronal cells in the context of the potential influence of REST. A series of OPRM1-luciferase promoter/reporter constructs were transfected into two neuronal cell models, neuroblastoma-derived SH-SY5Y cells and PC12 cells. In the former, endogenous levels of human mu-opioid receptor (hMOPr) mRNA were evaluated by real-time PCR. IGF-I up-regulated OPRM1 transcription in: PC12 cells lacking REST, in SH-SY5Y cells transfected with constructs deficient in the REST DNA binding element, or when REST was down-regulated in retinoic acid-differentiated cells. IGF-I activates the signal transducer and activator of transcription-3 signaling pathway and this transcription factor, binding to the signal transducer and activator of transcription-1/3 DNA element located in the promoter, increases OPRM1 transcription. We propose that a reduction in REST is a critical switch enabling IGF-I to up-regulate hMOPr. These findings help clarify how hMOPr expression is regulated in neuronal cells. [source]


Calsenilin interacts with transcriptional co-repressor C-terminal binding protein(s)

JOURNAL OF NEUROCHEMISTRY, Issue 4 2006
Nikhat F. Zaidi
Abstract Calsenilin/potassium channel-interacting protein (KChIP)3/ downstream regulatory element sequence antagonist modulator (DREAM) is a neuronal calcium-binding protein that has been shown to have multiple functions in the cell, including the regulation of presenilin processing, repression of transcription and modulation of A-type potassium channels. To gain a better understanding of the precise role of calsenilin in specific cellular compartments, an interactor hunt for proteins that bind to the N-terminal domain of calsenilin was carried out. Using a yeast two-hybrid system and co-immunoprecipitation studies, we have identified the transcriptional co-repressor C-terminal binding protein (CtBP)2 as an interactor for calsenilin and have shown that the two proteins can interact in vivo. In co-immunoprecipitation studies, calsenilin also interacted with CtBP1, a CtBP2 homolog. Our data also showed a calsenilin-dependent increase in c-fos protein levels in CtBP knockout fibroblasts, suggesting that CtBP may modulate the transcriptional repression of c-fos by calsenilin. Furthermore, the finding that histone deacetylase protein and activity were associated with the calsenilin,CtBP immunocomplex suggests a mechanism by which calsenilin,CtBP may act to repress transcription. Finally, we demonstrated that calsenilin and CtBP are present in synaptic vesicles and can interact in vivo. [source]


A novel repressor of nif and glnA expression in the methanogenic archaeon Methanococcus maripaludis

MOLECULAR MICROBIOLOGY, Issue 1 2003
Thomas J. Lie
Summary Nitrogen assimilation in the methanogenic archaeon Methanococcus maripaludis is regulated by transcriptional repression involving a palindromic ,nitrogen operator' repressor binding sequence. Here we report the isolation of the nitrogen repressor, NrpR, from M. maripaludis using DNA affinity purification. Deletion of the nrpR gene resulted in loss of nitrogen operator binding activity in cell extracts and loss of repression of nif (nitrogen- fixation) and glnA (glutamine synthetase) gene expression in vivo. Genetic complementation of the nrpR mutation restored all functions. NrpR contained a putative N-terminal winged helix,turn,helix motif followed by two mutually homologous domains of unknown function. Comparison of the migration of NrpR in gel-filtration chromatography with its subunit molecular weight (60 kDa) suggested that NrpR was a tetramer. Several lines of evidence suggested that the level of NrpR itself is not regulated, and the binding affinity of NrpR to the nitrogen operator is controlled by an unknown mechanism. Homologues of NrpR were found only in certain species in the kingdom Euryarchaeota. Full length homologues were found in Methanocaldococcus jannaschii and Methanothermobacter thermoautotrophicus, and homologues lacking one or more of the three polypeptide domains were found in Archaeoglobus fulgidus, Methanopyrus kandleri, Methanosarcina acetivorans, and Methanosarcina mazei. NrpR represents a new family of regulators unique to the Euryarchaeota. [source]


Global H3K9 dimethylation status is not affected by transcription, translation, or DNA replication in porcine zygotes

MOLECULAR REPRODUCTION & DEVELOPMENT, Issue 5 2010
Ki-Eun Park
Methylation of the lysine 9 residue of histone H3 (H3K9) is linked to transcriptional repression. The observed structure of chromatin in porcine and murine embryos is different with regard to H3K9 dimethylation status, leading to our hypothesis that the intracellular mechanisms responsible for H3K9 methylation would also differ between these two species. The objectives of this study were: (1) to determine the extent that DNA, mRNA, and protein synthesis serve in maintaining the asymmetrical distribution of dimethylated H3K9 in porcine zygotes, (2) determine the extent to which the intracellular localization of individual pronuclei correlated with H3K9 dimethylation status, and (3) to determine the abundance of transcripts encoding the histone methyltransferases, with H3K9 methylation activity, in porcine oocytes and embryos. Our findings are that (1) H3K9 dimethylation status is not affected by DNA replication, transcription, or protein synthesis, (2) the location of a pronucleus does not significantly affect the H3K9 dimethylation status of the chromatin within that pronucleus, and (3) the histone methyltransferases with activity for H3K9 differ in transcript abundance in porcine oocytes and cleavage stage embyros. These results support our hypothesis that there is a difference in intracellular mechanisms affecting dimethylation status of H3K9 between porcine and murine embryos. Mol. Reprod. Dev. 77: 420,429, 2010. © 2010 Wiley-Liss, Inc. [source]


Polymerization of the SAM domain of MAPKKK Ste11 from the budding yeast: Implications for efficient signaling through the MAPK cascades

PROTEIN SCIENCE, Issue 3 2005
Surajit Bhattacharjya
Abstract The sterile ,-motif (SAM) is a protein module ,70 residues long and mainly involved in the protein,protein interactions of cell signaling and transcriptional repression. The SAM domain of the yeast MAPKKK Ste11 has a well-folded dimeric structure in solution. Interestingly, the well-folded dimer of the Ste11 SAM undergoes a time-dependent self-assembly upon lowering of the pH, leading to the formation of high molecular weight oligomers. The oligomeric structures rapidly disassemble to the well-folded dimer upon reversal of the pH to close to neutral conditions. Circular dichroism (CD) and atomic force microscopy (AFM) experiments demonstrate that the oligomeric structure formed at pH 5.0 appears to be highly helical and has architecture akin to proto-fibrils. Residue-specific kinetics of pH-triggered oligomerization obtained from real-time 15N- 1H HSQC experiments indicate that the dimer-oligomer transition appears to involve all residues of the well-folded dimeric structure of the Ste11 SAM. Very interestingly, the interactions of the Ste11 and Ste50 SAM domains also lead to the formation of non-homogeneous hetero-complexes with significant populations of high molecular weight aggregates. AFM imaging shows that the Ste11-Ste50 hetero-polymeric aggregates assume the shapes of circular nano-particles with dimensions of 50,60 nano-meters (nm), in contrast to the proto-fibrils formed by the Ste11 SAM domain alone. Such intrinsic propensity for dimer to oligomer transition of the Ste50-binding SAM domain of Ste11 may endow the MAPKKK Ste11 with unique functional properties required for efficient and high fidelity signal transduction in the budding yeast. [source]


NtSET1, a member of a newly identified subgroup of plant SET-domain-containing proteins, is chromatin-associated and its ectopic overexpression inhibits tobacco plant growth

THE PLANT JOURNAL, Issue 4 2001
Wen-Hui Shen
Summary The SET- and chromo-domains are recognized as signature motifs for proteins that contribute to epigenetic control of gene expression through effects on the regional organization of chromatin structure. This paper reports the identification of a novel subgroup of SET-domain-containing proteins in tobacco and Arabidopsis, which show highest homologies with the Drosophila position-effect-variegation repressor protein SU(VAR)3,9 and the yeast centromer silencing protein CLR4. The tobacco SET-domain-containing protein (NtSET1) was fused to the green fluorescence protein (GFP) that serves as a visual marker for localization of the recombinant protein in living cells. Whereas control GFP protein alone was uniformly dispersed within the nucleus and cytoplasm, the NtSET1-GFP fusion protein showed a non-uniform localization to multiple nuclear regions in interphase tobacco TBY2 cells. During mitosis, the NtSET1-GFP associated with condensed chromosomes with a non-random distribution. The NtSET1 thus appears to have distinct target regions in the plant chromatin. Overexpression of the NtSET1-GFP in transgenic tobacco inhibited plant growth, implicating the possible involvement of the NtSET1 in transcriptional repression of growth control genes through the formation of higher-order chromatin domains. [source]


Dynamic regulation of DNA methylation coupled transcriptional repression: BDNF regulation by MeCP2

BIOESSAYS, Issue 3 2004
Paul A. Wade
A recurrent theme in eukaryotic genome regulation stipulates that the properties of DNA are strongly influenced by the nucleoprotein complex into which it is assembled. Methylation of cytosine residues in vertebrate genomes has been implicated in influencing the assembly of locally repressive chromatin architecture. Current models suggest that covalent modification of DNA results in heritable, long-term transcriptional silencing. In October of 2003, two manuscripts1,2 were published that challenge important aspects of this model, suggesting that modulation of both DNA methylation itself, as well as the machinery implicated in its interpretation, are involved in acute gene regulation. BioEssays 26:217,220, 2004. © 2004 Wiley Periodicals, Inc. [source]


Bacterial exotoxins downregulate cathelicidin (hCAP-18/LL-37) and human ,-defensin 1 (HBD-1) expression in the intestinal epithelial cells

CELLULAR MICROBIOLOGY, Issue 12 2008
Krishnendu Chakraborty
Summary Cathelicidin (hCAP-18/LL-37) and ,-defensin 1 (HBD-1) are human antimicrobial peptides (AMPs) with high basal expression levels, which form the first line of host defence against infections over the epithelial surfaces. The antimicrobial functions owe to their direct microbicidal effects as well as the immunomodulatory role. Pathogenic microorganisms have developed multiple modalities including transcriptional repression to combat this arm of the host immune response. The precise mechanisms and the pathogen-derived molecules responsible for transcriptional downregulation remain unknown. Here, we have shown that enteric pathogens suppress LL-37 and HBD-1 expression in the intestinal epithelial cells (IECs) with Vibrio cholerae and enterotoxigenic Escherichia coli (ETEC) exerting the most dramatic effects. Cholera toxin (CT) and labile toxin (LT), the major virulence proteins of V. cholerae and ETEC, respectively, are predominantly responsible for these effects, both in vitro and in vivo. CT transcriptionally downregulates the AMPs by activating several intracellular signalling pathways involving protein kinase A (PKA), ERK MAPKinase and Cox-2 downstream of cAMP accumulation and inducible cAMP early repressor (ICER) may mediate this role of CT, at least in part. This is the first report to show transcriptional repression of the AMPs through the activation of cellular signal transduction pathways by well-known virulence proteins of pathogenic microorganisms. [source]