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See detailPP2A regulatory subunit Balpha controls endothelial contractility and vessel lumen integrity via regulation of HDAC7.
Martin, Maud ULg; Geudens, Ilse; Bruyr, Jonathan et al

in EMBO Journal (2013)

To supply tissues with nutrients and oxygen, the cardiovascular system forms a seamless, hierarchically branched, network of lumenized tubes. Here, we show that maintenance of patent vessel lumens ... [more ▼]

To supply tissues with nutrients and oxygen, the cardiovascular system forms a seamless, hierarchically branched, network of lumenized tubes. Here, we show that maintenance of patent vessel lumens requires the Balpha regulatory subunit of protein phosphatase 2A (PP2A). Deficiency of Balpha in zebrafish precludes vascular lumen stabilization resulting in perfusion defects. Similarly, inactivation of PP2A-Balpha in cultured ECs induces tubulogenesis failure due to alteration of cytoskeleton dynamics, actomyosin contractility and maturation of cell-extracellular matrix (ECM) contacts. Mechanistically, we show that PP2A-Balpha controls the activity of HDAC7, an essential transcriptional regulator of vascular stability. In the absence of PP2A-Balpha, transcriptional repression by HDAC7 is abrogated leading to enhanced expression of the cytoskeleton adaptor protein ArgBP2. ArgBP2 hyperactivates RhoA causing inadequate rearrangements of the EC actomyosin cytoskeleton. This study unravels the first specific role for a PP2A holoenzyme in development: the PP2A-Balpha/HDAC7/ArgBP2 axis maintains vascular lumens by balancing endothelial cytoskeletal dynamics and cell-matrix adhesion. [less ▲]

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See detailNuclear export of histone deacetylase 7 during thymic selection is required for immune self-tolerance.
Kasler, Herbert G.; Lim, Hyung W.; Mottet, Denis ULg et al

in EMBO Journal (2012)

Histone deacetylase 7 (HDAC7) is a T-cell receptor (TCR) signal-dependent regulator of differentiation that is highly expressed in CD4/CD8 double-positive (DP) thymocytes. Here, we examine the effect of ... [more ▼]

Histone deacetylase 7 (HDAC7) is a T-cell receptor (TCR) signal-dependent regulator of differentiation that is highly expressed in CD4/CD8 double-positive (DP) thymocytes. Here, we examine the effect of blocking TCR-dependent nuclear export of HDAC7 during thymic selection, through expression of a signal-resistant mutant of HDAC7 (HDAC7-DeltaP) in thymocytes. We find that HDAC7-DeltaP transgenic thymocytes exhibit a profound block in negative thymic selection, but can still undergo positive selection, resulting in the escape of autoreactive T cells into the periphery. Gene expression profiling reveals a comprehensive suppression of the negative selection-associated gene expression programme in DP thymocytes, associated with a defect in the activation of MAP kinase pathways by TCR signals. The consequence of this block in vivo is a lethal autoimmune syndrome involving the exocrine pancreas and other abdominal organs. These experiments establish a novel molecular model of autoimmunity and cast new light on the relationship between thymic selection and immune self-tolerance. [less ▲]

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See detailMutant huntingtin-impaired degradation of beta-catenin causes neurotoxicity in Huntington's disease.
Godin, Juliette ULg; Poizat, Ghislaine; Hickey, Myriam et al

in EMBO Journal (2010), 29(14)

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See detailAntibody evasion by the N terminus of murid herpesvirus-4 glycoprotein B.
Gillet, Laurent ULg; Stevenson, Philip G

in EMBO Journal (2007), 26(24), 5131-42

Herpesviruses characteristically transmit infection from immune hosts. Although their success in escaping neutralization by pre-formed antibody is indisputable, the underlying molecular mechanisms remain ... [more ▼]

Herpesviruses characteristically transmit infection from immune hosts. Although their success in escaping neutralization by pre-formed antibody is indisputable, the underlying molecular mechanisms remain largely unknown. Glycoprotein B (gB) is the most conserved component of the herpesvirus entry machinery and its N terminus (gB-NT) is a common neutralization target. We used murid herpesvirus-4 to determine how gB-NT contributes to the virus-antibody interaction. Deleting gB-NT had no obvious impact on virus replication, but paradoxically increased virion neutralization by immune sera. This reflected greater antibody access to neutralization epitopes on gH/gL, with which gB was associated. gB-NT itself was variably protected against antibody by O-linked glycans; on virions from epithelial cells it was protected almost completely. gB-NT therefore provides a protective and largely protected cover for a vulnerable part of gH/gL. The conservation of predicted glycosylation sites in other mammalian herpesvirus gB-NTs suggests that this evasion mechanism is widespread. Interestingly, the gB-NT glycans that blocked antibody binding could be targeted for neutralization instead by a lectin, suggesting a means of therapeutic counterattack. [less ▲]

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See detailPhosphorylation At Ser244 By Ck1 Determines Nuclear Localization And Substrate Targeting Of Pkd2
Von Blume, J.; Knippschild, U.; Dequiedt, Franck ULg et al

in Embo Journal (2007), 26(22),

Protein kinase D2 (PKD2), a member of the PKD family of serine/threonine kinases, is localized in various subcellular compartments including the nucleus where the kinase accumulates upon activation of G ... [more ▼]

Protein kinase D2 (PKD2), a member of the PKD family of serine/threonine kinases, is localized in various subcellular compartments including the nucleus where the kinase accumulates upon activation of G-protein-coupled receptors. We define three critical post-translational modifications required for nuclear accumulation of PKD2 in response to activation of the CCK2 receptor (CCK2R): phosphorylation at Ser706 and Ser710 within the activation loop by PKC eta leading to catalytic activity and phosphorylation at Ser244 within the zinc-finger domain, which is crucial for blocking nuclear export of active PKD2 by preventing its interaction with the Crm-1 export machinery. We identify CK1delta and epsilon as upstream activated kinases by CCK2R that phosphorylate PKD2 at Ser244. Moreover, nuclear accumulation of active PKD2 is a prerequisite for efficient phosphorylation of its nuclear substrate, HDAC7. Only nuclear, active PKD2 mediates CCK2R-induced HDAC7 phosphorylation and Nur77 expression. Thus, we define a novel, compartment-specific signal transduction pathway downstream of CCK2R that phosphorylates PKD2 at three specific sites, results in nuclear accumulation of the active kinase and culminates in efficient phosphorylation of nuclear PKD2 substrates in human gastric cancer cells. [less ▲]

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See detailRecruitment Of Chromatin-Modifying Enzymes By Ctip2 Promotes Hiv-1 Transcriptional Silencing
Marban, C.; Suzanne, S.; Dequiedt, Franck ULg et al

in Embo Journal (2007), 26(2),

Following entry and reverse transcription, the HIV-1 genome is integrated into the host genome. In contrast to productively infected cells, latently infected cells frequently harbor HIV-1 genomes ... [more ▼]

Following entry and reverse transcription, the HIV-1 genome is integrated into the host genome. In contrast to productively infected cells, latently infected cells frequently harbor HIV-1 genomes integrated in heterochromatic structures, allowing persistence of transcriptionally silent proviruses. Microglial cells are the main HIV-1 target cells in the central nervous system and constitute an important reservoir for viral pathogenesis. In the present work, we show that, in microglial cells, the co-repressor COUP-TF interacting protein 2 (CTIP2) recruits a multienzymatic chromatin-modifying complex and establishes a heterochromatic environment at the HIV-1 promoter. We report that CTIP2 recruits histone deacetylase (HDAC)1 and HDAC2 to promote local histone H3 deacetylation at the HIV-1 promoter region. In addition, DNA-bound CTIP2 also associates with the histone methyltransferase SUV39H1, which increases local histone H3 lysine 9 methylation. This allows concomitant recruitment of HP1 proteins to the viral promoter and formation of local heterochromatin, leading to HIV-1 silencing. Altogether, our findings uncover new therapeutic opportunities for purging latent HIV-1 viruses from their cellular reservoirs. [less ▲]

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See detailG1 checkpoint failure and increased tumor susceptibility in mice lacking the novel p53 target Ptprv.
Doumont, Gilles; Martoriati, Alain; Beekman, Chantal et al

in EMBO Journal (2005), 24(17), 3093-3103

In response to DNA damage, p53 activates a G1 cell cycle checkpoint, in part through induction of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). Here we report the identification of a new direct ... [more ▼]

In response to DNA damage, p53 activates a G1 cell cycle checkpoint, in part through induction of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). Here we report the identification of a new direct p53 target, Ptprv (or ESP), encoding a transmembrane tyrosine phosphatase. Ptprv transcription is dramatically and preferentially increased in cultured cells undergoing p53-dependent cell cycle arrest, but not in cells undergoing p53-mediated apoptosis. This observation was further confirmed in vivo using a Ptprv null-reporter mouse line. A p53-responsive element is present in the Ptprv promoter and p53 is recruited to this site in vivo. Importantly, while p53-dependent apoptosis is intact in mice lacking Ptprv, Ptprv-null fibroblasts and epithelial cells of the small intestine are defective in G1 checkpoint control. Thus, Ptprv is a new direct p53 target and a key mediator of p53-induced cell cycle arrest. Finally, Ptprv loss enhances the formation of epidermal papillomas after exposure to chemical carcinogens, suggesting that Ptprv acts to suppress tumor formation in vivo. [less ▲]

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See detailGlycoprotein G isoforms from some alphaherpesviruses function as broad-spectrum chemokine binding proteins
Bryant, N. A.; Davis-Poynter, N.; Vanderplasschen, Alain ULg et al

in EMBO Journal (2003), 22

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See detailTwo distinct myosin light chain structures are induced by specific variations within the bound IQ motifs-functional implications
Terrak, Mohammed ULg; Wu, G.; Stafford, W. F. et al

in EMBO Journal (2003), 22(3), 362-71

IQ motifs are widespread in nature. Mlc1p is a calmodulin-like myosin light chain that binds to IQ motifs of a class V myosin, Myo2p, and an IQGAP-related protein, Iqg1p, playing a role in polarized ... [more ▼]

IQ motifs are widespread in nature. Mlc1p is a calmodulin-like myosin light chain that binds to IQ motifs of a class V myosin, Myo2p, and an IQGAP-related protein, Iqg1p, playing a role in polarized growth and cytokinesis in Saccharomyces cerevisiae. The crystal structures of Mlc1p bound to IQ2 and IQ4 of Myo2p differ dramatically. When bound to IQ2, Mlc1p adopts a compact conformation in which both the N- and C-lobes interact with the IQ motif. However, in the complex with IQ4, the N-lobe no longer interacts with the IQ motif, resulting in an extended conformation of Mlc1p. The two light chain structures relate to two distinct subfamilies of IQ motifs, one of which does not interact with the N-lobes of calmodulin-like light chains. The correlation between light chain structure and IQ sequence is demonstrated further by sedimentation velocity analysis of complexes of Mlc1p with IQ motifs from Myo2p and Iqg1p. The resulting 'free' N-lobes of myosin light chains in the extended conformation could mediate the formation of ternary complexes during protein localization and/or partner recruitment. [less ▲]

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See detailControl of proliferation, endoreduplication and differentiation by the Arabidopsis E2Fa-DPa transcription factor
De Veylder, L.; Beeckman, T.; Beemster, G. T. S. et al

in EMBO Journal (2002), 21(6), 1360-1368

New plant cells arise at the meristems, where they divide a few times before they leave the cell-cycle program and start to differentiate. Here we show that the E2Fa-DPa transcription factor of ... [more ▼]

New plant cells arise at the meristems, where they divide a few times before they leave the cell-cycle program and start to differentiate. Here we show that the E2Fa-DPa transcription factor of Arabidopsis thaliana is a key regulator determining the proliferative status of plant cells. Ectopic expression of E2Fa induced sustained cell proliferation in normally differentiated cotyledon and hypocotyl cells. The phenotype was enhanced strongly by the co-expression of E2Fa with its dimerization partner, DPa. In endoreduplicating cells, E2Fa-DPa also caused extra DNA replication that was correlated with transcriptional induction of S phase genes. Because E2Fa-DPa transgenic plants arrested early in development, we argue that controlled exit of the cell cycle is a prerequisite for normal plant development. [less ▲]

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See detailBox C/D small nucleolar RNA trafficking involves small nucleolar RNP proteins, nucleolar factors and a novel nuclear domain.
Verheggen, C.; Mouaikel, J.; Thiry, Marc ULg et al

in EMBO Journal (2001), 20(19), 5480-90

Nucleolar localization of box C/D small nucleolar (sno) RNAs requires the box C/D motif and, in vertebrates, involves transit through Cajal bodies (CB). We report that in yeast, overexpression of a box C ... [more ▼]

Nucleolar localization of box C/D small nucleolar (sno) RNAs requires the box C/D motif and, in vertebrates, involves transit through Cajal bodies (CB). We report that in yeast, overexpression of a box C/D reporter leads to a block in the localization pathway with snoRNA accumulation in a specific sub-nucleolar structure, the nucleolar body (NB). The human survival of motor neuron protein (SMN), a marker of gems/CB, specifically localizes to the NB when expressed in yeast, supporting similarities between these structures. Box C/D snoRNA accumulation in the NB was decreased by mutation of Srp40 and increased by mutation of Nsr1p, two related nucleolar proteins that are homologous to human Nopp140 and nucleolin, respectively. Box C/D snoRNAs also failed to accumulate in the NB, and became delocalized to the nucleoplasm, upon depletion of any of the core snoRNP proteins, Nop1p/fibrillarin, Snu13p, Nop56p and Nop5p/Nop58p. We conclude that snoRNP assembly occurs either in the nucleoplasm, or during transit of snoRNAs through the NB, followed by routing of the complete snoRNP to functional sites of ribosome synthesis. [less ▲]

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See detailPLENA and FARINELLI: redundancy and regulatory interactions between two Antirrhinum MADS-box factors controlling flower development.
Davies, B.; Motte, Patrick ULg; Keck, E. et al

in EMBO Journal (1999), 18(14), 4023-34

We report the discovery of an Antirrhinum MADS-box gene, FARINELLI (FAR), and the isolation of far mutants by a reverse genetic screen. Despite striking similarities between FAR and the class C MADS-box ... [more ▼]

We report the discovery of an Antirrhinum MADS-box gene, FARINELLI (FAR), and the isolation of far mutants by a reverse genetic screen. Despite striking similarities between FAR and the class C MADS-box gene PLENA (PLE), the phenotypes of their respective mutants are dramatically different. Unlike ple mutants, which show homeotic conversion of reproductive organs to perianth organs and a loss of floral determinacy, far mutants have normal flowers which are partially male-sterile. Expression studies of PLE and FAR, in wild-type and mutant backgrounds, show complex interactions between the two genes. Double mutant analysis reveals an unexpected, redundant negative control over the B-function MADS-box genes. This feature of the two Antirrhinum C-function-like genes is markedly different from the control of the inner boundary of the B-function expression domain in Arabidopsis, and we propose and discuss a model to account for these differences. The difference in phenotypes of mutants in two highly related genes illustrates the importance of the position within the regulatory network in determining gene function. [less ▲]

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See detailA domain of TEL conserved in a subset of ETS proteins defines a specific oligomerization interface essential to the mitogenic properties of the TEL-PDGFR beta oncoprotein.
Jousset, C.; Carron, C.; Boureux, A. et al

in EMBO Journal (1997)

TEL is a novel member of the ETS family of transcriptional regulators which is frequently involved in human leukemias as the result of specific chromosomal translocations. This study shows that the amino ... [more ▼]

TEL is a novel member of the ETS family of transcriptional regulators which is frequently involved in human leukemias as the result of specific chromosomal translocations. This study shows that the amino-terminal domain conserved in a subset of the ETS proteins has evolved to generate a specialized protein-protein interaction interface which is likely to be an important determinant of their specificity as transcriptional regulators. [less ▲]

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See detailComplete Nucleotide Sequence Of Saccharomyces Cerevisiae Chromosome X
Galibert, F.; Alexandraki, D.; Baur, A. et al

in Embo Journal (1996), 15(9),

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See detailThe 3-D structure of a zinc metallo-beta-lactamase from Bacillus cereus reveals a new type of protein fold
Carfi, A.; Pares, S.; Duée, E. et al

in EMBO Journal (1995), 14(20), 4914-4921

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See detailThe oncoprotein Bcl-3 can facilitate NF-kappa B-mediated transactivation by removing inhibiting p50 homodimers from select kappa B sites.
Franzoso, G.; Bours, Vincent ULg; Azarenko, V. et al

in EMBO Journal (1993), 12(10), 3893-901

Previously we have proposed a role for Bcl-3 in facilitating transactivation through kappa B sites by counteracting the inhibitory effects of bound, non-transactivating homodimers of the p50 subunit of NF ... [more ▼]

Previously we have proposed a role for Bcl-3 in facilitating transactivation through kappa B sites by counteracting the inhibitory effects of bound, non-transactivating homodimers of the p50 subunit of NF-kappa B. Such homodimers are abundant for example in nuclei of unstimulated primary T cells. Here we extend the model and provide new evidence which fulfills a number of predictions. (i) Bcl-3 preferentially targets p50 homodimers over NF-kappa B heterodimers since the homodimers are completely dissociated from kappa B sites at concentrations of Bcl-3 which do not affect NF-kappa B. (ii) Select kappa B sites associate very strongly and stably with p50 homodimers, completely preventing binding by NF-kappa B. Such kappa B sites are likely candidates for regulation by p50 homodimers and Bcl-3. (iii) Bcl-3 and p50 can be co-localized in the nucleus, a requirement for active removal of homodimers from their binding sites in vivo. (iv) The ankyrin repeat domain of Bcl-3 is sufficient for the reversal of p50 homodimer-mediated inhibition, correlating with the ability of this domain alone to inhibit p50 binding to kappa B sites in vitro. Our data support the model that induction of nuclear Bcl-3 may be required during cellular stimulation to actively remove stably bound p50 homodimers from certain kappa B sites in order to allow transactivating NF-kappa B complexes to engage. This exact mechanism is demonstrated with in vitro experiments. [less ▲]

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See detailClustered organization of homologous KRAB zinc-finger genes with enhanced expression in human T lymphoid cells
Bellefroid, Eric J; Marine, Jean-Christophe; Ried, Thomas et al

in EMBO Journal (1993), 12(4), 1363-1374

KRAB zinc-finger proteins (KRAB-ZFPs) constitute a large subfamily of ZFPs of the Krüppel C2H2 type. KRAB (Krüppel-associated box) is an evolutionarily conserved protein domain found N-terminally with ... [more ▼]

KRAB zinc-finger proteins (KRAB-ZFPs) constitute a large subfamily of ZFPs of the Krüppel C2H2 type. KRAB (Krüppel-associated box) is an evolutionarily conserved protein domain found N-terminally with respect to the finger repeats. We report here the characterization of a particular subgroup of highly related human KRAB-ZFPs. ZNF91 is one representative of this subgroup and contains 35 contiguous finger repeats at its C-terminus. Three mRNA isoforms with sequence identity to ZNF91 were isolated by the polymerase chain reaction. These encode proteins with a KRAB domain present, partially deleted or absent. Five genomic fragments were characterized, each encoding part of a gene: the ZNF91 gene or one of four distinct, related KRAB-ZFP genes. All exhibit a common exon/intron organization with the variant zinc finger repeats organized in a single exon and the KRAB domain encoded by two separate exons. This positioning of introns supports the hypothesis that the mRNA isoforms encoding polypeptides with variability in the KRAB domain could arise by alternative splicing. By in situ chromosomal mapping studies and by analysis of fragments from a human genomic yeast artificial chromosome library containing KRAB-ZFP genes, we show that these genes occur in clusters; in particular, a gene complex containing over 40 genes has been identified in chromosomal region 19p12-p13.1. These ZNF91-related genes probably arose late during evolution since no homologous genes are detected in the mouse and rat genomes. Although the transcription of members of this KRAB-ZFP gene subgroup is detectable in all human tissues, their expression is significantly higher in human T lymphoid cells. [less ▲]

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See detailGLOBOSA: a homeotic gene which interacts with DEFICIENS in the control of Antirrhinum floral organogenesis.
Trobner, W.; Ramirez, L.; Motte, Patrick ULg et al

in EMBO Journal (1992), 11(13), 4693-704

GLOBOSA (GLO) is a homeotic gene whose mutants show sepaloid petals and carpelloid stamens. The similarity of Glo mutants to those of the DEFICIENS (DEFA) gene suggests that the two genes have comparable ... [more ▼]

GLOBOSA (GLO) is a homeotic gene whose mutants show sepaloid petals and carpelloid stamens. The similarity of Glo mutants to those of the DEFICIENS (DEFA) gene suggests that the two genes have comparable functions in floral morphogenesis. The GLO cDNA has been cloned by virtue of its homology to the MADS-box, a conserved DNA-binding domain also contained in the DEFA gene. We have determined the structure of the wild type GLO gene as well as of several glo mutant alleles which contain transposable element insertions responsible for somatic and germinal instability of Glo mutants. Analyses of the temporal and spatial expression patterns of the DEFA and GLO genes during development of wild type flowers and in flowers of various stable and unstable defA and glo alleles indicate independent induction of DEFA and GLO transcription. In contrast, organ-specific up-regulation of the two genes in petals and stamens depends on expression of both DEFA and GLO. In vitro DNA-binding studies were used to demonstrate that the DEFA and GLO proteins specifically bind, as a heterodimer, to motifs in the promoters of both genes. A model is presented which proposes both combinatorial and cross-regulatory interactions between the DEFA and GLO genes during petal and stamen organogenesis in the second and third whorls of the flower. The function of the two genes controlling determinate growth of the floral meristem is also discussed. [less ▲]

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See detailCooperation Between Bovine Leukemia-Virus Transactivator Protein And Ha-Ras Oncogene Product In Cellular-Transformation
Willems, Luc ULg; Heremans, H.; Chen, G. et al

in Embo Journal (1990), 9(5),

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See detailActivity of two different silencer elements of the chicken lysozyme gene can be compensated by enhancer elements.
Baniahmad, A.; Muller, Marc ULg; Steiner, C. et al

in EMBO Journal (1987), 6(8), 2297-303

The chicken lysozyme gene is constitutively expressed in macrophages. Transfection of recombinant genes containing different portions of the lysozyme 5' upstream region revealed the existence of two ... [more ▼]

The chicken lysozyme gene is constitutively expressed in macrophages. Transfection of recombinant genes containing different portions of the lysozyme 5' upstream region revealed the existence of two negative transcriptional elements within 1 kb upstream of the start sites. Both elements placed upstream or downstream of a heterologous promoter-gene unit repress transcription independent of their orientation and are therefore called silencer elements, although their repressing activities 3' of the gene are reduced. One silencer (N-1.0 kb) at position -1 kb consists of the central region of the chicken middle repetitive sequence element CR1 and can be divided into two functional domains. N-1.0 kb is active in all cell types tested. The other silencer (N-0.25 kb) at position -0.25 kb shows reduced activity in primary macrophages. Despite their different specificities, the activity of both silencer elements can be influenced similarly. An inverse linear relationship between the transcriptional activity of the tested constructs and the potential inhibition by the silencer elements was found: weak transcription units can be strongly repressed, whereas strong transcription units can be only weakly repressed. Such a mechanism may help to turn off completely a particular gene in situations or tissues where strong positive regulators are inactive. [less ▲]

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