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See detailThe glucocorticoid receptor inhibits the human prolactin gene expression by interference with Pit-1 activity
Nalda, Asunción M; Martial, Joseph ULg; Muller, Marc ULg

in Molecular & Cellular Endocrinology (1997), 134(2), 129-37

Glucocorticoids have been shown to inhibit the activity of the human prolactin (hPRL) promoter. Using transient expression experiments in rat pituitary cells, we located the sequence conferring ... [more ▼]

Glucocorticoids have been shown to inhibit the activity of the human prolactin (hPRL) promoter. Using transient expression experiments in rat pituitary cells, we located the sequence conferring glucocorticoid inhibition to a region which contains Pit-1 binding sites, responsible for pituitary-specific expression, but does not seem to contain a glucocorticoid receptor (GR) binding site. Co-transfection experiments in non-pituitary cell lines, using expression vectors for Pit-1 and different mutants of the human GR show that inhibition of the hPRL gene is seen only in the presence of Pit-1 and GR, and that the DNA binding function of the receptor is not required. Immunoprecipitation studies show that either anti-GR or anti-Pit-1 antibodies are able to co-precipitate GR and Pit-1, suggesting an interaction between these factors. We conclude that the activated GR functionally interferes with the pituitary specific factor Pit-1, thereby leading to the observed transcriptional repression. [less ▲]

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See detailA one-nucleotide difference in a cAMP and phorbol ester response element leads to differential regulation of the human chorionic somatomammotropin A and B gene transcription
Oury, Cécile ULg; Alsat, E.; Jacquemin, P. et al

in Journal of Molecular Endocrinology (1997), 18(2), 87-99

Human chorionic somatomammotropin (hCS) is encoded by two highly related genes, hCS-A and hCS-B, located in the hGH/hCS gene locus. Both genes are expressed in the syncytiotrophoblast layer of the ... [more ▼]

Human chorionic somatomammotropin (hCS) is encoded by two highly related genes, hCS-A and hCS-B, located in the hGH/hCS gene locus. Both genes are expressed in the syncytiotrophoblast layer of the placenta and hCS release from trophoblast cells is known to be increased by cAMP and phorbol esters. However, it remains unclear whether this regulation acts at the level of hCS gene expression or secretion and whether both genes are affected. We examined the effects of cAMP and phorbol 12-myristate 13-acetate (PMA) on the transcription of the hCS-A and hCS-B genes. Transient expression experiments revealed a 7 bp cAMP- and PMA-responsive element (CRElhCS-A) spanning nucleotides-1102 to -1096 upstream of the hCS-A gene. In contrast, the homologous sequence upstream of hCS-B (CRElhCS-B), differing from CRElhCS-A by a single substitution, shows little or no response to cAMP. In band-shift assays, the CRElhCS-A oligonucleotide was shown to bind two factors related to CREBP and AP-1, whereas CRElhCS-B only competes for one of these complexes. Finally, Southwestern analysis revealed that the CRElhCS-A element binds two ubiquitous proteins of 100 kDa and 47 kDa respectively, whereas CRElhCS-B interacts only with the 47 kDa protein. Taken together, these results suggest that a 47 kDa protein binding to the CRElhCS-A and CRElhCS-B elements is involved in the PMA response of the hCS-A and hCS-B genes, and a 100 kDa protein plays a crucial role in cAMP regulation of the hCS-A gene. [less ▲]

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See detailThe tilapia prolactin I gene: evolutionary conservation of the regulatory elements directing pituitary-specific expression
Poncelet, A. C.; Levavi-Sivan, B.; Muller, Marc ULg et al

in DNA & Cell Biology (1996), 15(8), 679-92

To study the elements involved in the pituitary specific transcriptional regulation of the tilapia prolactin I gene (tiPRL I), we have cloned and entirely sequenced a 3.4-kb genomic fragment immediately ... [more ▼]

To study the elements involved in the pituitary specific transcriptional regulation of the tilapia prolactin I gene (tiPRL I), we have cloned and entirely sequenced a 3.4-kb genomic fragment immediately upstream from the first exon. In footprinting experiments, three tilapia sequences are protected from DNase I digestion by rat pituitary extracts (base pair coordinates -643 to -593, -160 to -111, and -73 to -46). Computer analysis of the nucleotide sequence reveals significant homology to mammalian binding sites for Pit-1, a transcription factor that is known to mediate pituitary-specific expression of the PRL genes in mammals. The tiPRL I 5'-flanking sequences can direct transient expression of a linked luciferase reporter gene in transfected rat pituitary cell lines and tilapia pituitary primary cell cultures. Transient expression experiments with 5'-deletion mutants reveal three regulatory regions. Two have a stimulatory effect on transcription and one an inhibitory effect. Electrophoretic mobility-shift assays (EMSA) demonstrate that the rat Pit-1 factor specifically binds to tilapia DNA sequences. Several such tilapia Pit-1 binding sites mediate activation of a linked heterologous promoter in transfected rat and tilapia pituitary cells. As evidenced by EMSA, a Pit-1-like protein is present in tilapia pituitary extracts. All these data point to a high conservation of the molecular mechanisms involved in pituitary-specific expression of the PRL genes in vertebrates. [less ▲]

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See detailDNA bending by the silencer protein NeP1 is modulated by TR and RXR.
Arnold, R.; Burcin, M.; Kaiser, Bruno ULg et al

in Nucleic Acids Research (1996), 24(14), 2640-7

NeP1 binds to the F1 silencer element of the chicken lysozyme gene and, in the presence of TR, v-ERBA or RAR, synergistically represses transcriptional activity. This repression involves a silencing ... [more ▼]

NeP1 binds to the F1 silencer element of the chicken lysozyme gene and, in the presence of TR, v-ERBA or RAR, synergistically represses transcriptional activity. This repression involves a silencing mechanism acting independently of the relative promoter position. Here we show that NeP1 alone can induce a significant directed bend on DNA. The chicken homologue of human NeP1, CTCF, shows identical binding and bending properties. In contrast, the isolated DNA binding domain of CTCF efficiently binds DNA, but fails to confer bending. Similarly, the TR-RXR hetero- or homodimer, binding adjacent to NeP1 at the F2 sequence, do not show significant DNA bending. The binding of the T3 ligand to TR changes neither the magnitude nor the direction of the NeP1 induced bend. However, when all factors are bound simultaneously as a quaternary complex, the TR-RXR heterodimer changes the location of the bend center, the flexure angle and the bending direction. [less ▲]

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See detailEnhancement of nuclear receptor transcriptional signalling.
Renkawitz, Rainer; Kaltschmidt, Christian; Leers, Joerg et al

in Journal of Steroid Biochemistry & Molecular Biology (1996), 56(1-6 Spec No), 39-45

Glucocorticoids and thyroid hormones induce complex responses in about every mammalian tissue. These effects are mediated by the transcription factor function of the corresponding nuclear receptors, which ... [more ▼]

Glucocorticoids and thyroid hormones induce complex responses in about every mammalian tissue. These effects are mediated by the transcription factor function of the corresponding nuclear receptors, which in most cases achieve the observed regulatory strength in synergy with other factors. Here we describe the functional interaction of the glucocorticoid receptor (GR) with liver-specific transcription factors, the functional synergy of GR with the thyroid hormone receptor (TR), the synergizing sub-domains of the TR, and finally the direct interaction of the GR with other proteins. [less ▲]

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See detailThe enhancers of the human placental lactogen B, A, and L genes: progressive activation during in vitro trophoblast differentiation and importance of the DF-3 element in determining their respective activities
Jacquemin, P.; Alsat, E.; Oury, Cécile ULg et al

in DNA & Cell Biology (1996), 15(10), 845-54

The hCS-A and hCS-B genes encoding human chorionic somatomammotropin and the related hCS-L gene are very similar in their coding and flanking sequences. For each of these genes, downstream enhancers ... [more ▼]

The hCS-A and hCS-B genes encoding human chorionic somatomammotropin and the related hCS-L gene are very similar in their coding and flanking sequences. For each of these genes, downstream enhancers, varying in strength, have been identified with the help of cytotrophoblast-derived JEG-3 cells, which do not express the hCS genes. Here we study the activity of the hCS enhancers in human syncytiotrophoblast in primary culture, which naturally expresses the hCS genes. We show that the activity of the hCS-B gene enhancer is mediated by two elements, DF-3 and DF-4, whereas the hCS-L and hCS-A gene enhancers display weaker activity due to mutations in their respective DF-3 sites. Replacement of the hCS-B DF-3 site with the homologous hCS-A sequence causes hCS-B enhancer activity to decrease. Primary cytotrophoblasts differentiate in culture to form the syncytiotrophoblast. We show that during this process the production of hCS progressively increases and that concomitantly all three hCS enhancers are progressively activated. A targeted mutation in the 3' part of the DF-4 element abolishes the binding of a protein present only in syncytiotrophoblast extracts and inactivates the DF-4 element. Thus, a direct correlation exists between the appearance of this syncytiotrophoblast-specific protein and hCS enhancer activity. This primary culture model proves useful in studying the regulation of the hCS genes. [less ▲]

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See detailTwo silencing sub-domains of v-erbA synergize with each other, but not with RXR.
Martin, Bernd; Renkawitz, Rainer; Muller, Marc ULg

in Nucleic Acids Research (1994), 22(23), 4898-905

The thyroid hormone receptor (TR) and the retinoic acid receptor (RAR) induce gene expression in the presence of specific ligand and repress transcription in the absence of hormone. This repression is ... [more ▼]

The thyroid hormone receptor (TR) and the retinoic acid receptor (RAR) induce gene expression in the presence of specific ligand and repress transcription in the absence of hormone. This repression is mediated by an active silencing mechanism rather then by interference with DNA binding activators. V-erbA, a variant form of TR which is unable to bind hormone, represents a constitutive repressor. Here we show, using fusion proteins with the GAL4 DNA binding domain, that the minimal silencing domain of v-erbA extends from amino acids 389 to 632 and that internal deletions within this domain retain at least some repression function. Co-transfection experiments of different deletion mutants indicate that the silencing domain is composed of at least two sub-domains which are non-functional when tested individually. When combined in a heterodimeric complex, they synergize such that silencing activity is regained. In contrast to the retinoic acid receptor the retinoid X receptor does not contain a silencing domain. In addition it is unable to cooperate with the repression function of TR or v-erbA in a heterodimer. [less ▲]

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See detailA thyroid hormone receptor-dependent glucocorticoid induction.
Leers, Joerg; Steiner, Christoff; Renkawitz, Rainer et al

in Molecular Endocrinology (Baltimore, Md.) (1994), 8(4), 440-7

Glucocorticoid and thyroid hormones exert their effects in many body tissues by binding to their respective receptors. The search for possible cross-talking mechanisms in overlapping target cells led to ... [more ▼]

Glucocorticoid and thyroid hormones exert their effects in many body tissues by binding to their respective receptors. The search for possible cross-talking mechanisms in overlapping target cells led to the discovery of synergism between a thyroid hormone receptor-binding site and a cryptic glucocorticoid-responsive element. Glucocorticoid responsiveness could only be detected in the presence of thyroid hormone and its receptor. This synergism requires the glucocorticoid receptor (GR) DNA-binding domain and is mediated by the transactivation domains. We found that synergism also occurs when the thyroid hormone receptor is replaced by the retinoic acid receptor or the GR is replaced by the progesterone receptor. Synergism is qualitatively independent of the type of thyroid hormone receptor-binding site and promoter. In several combinations of promoter and response elements, including a retinoic acid response element, T3 induction was only seen in the presence of the cryptic glucocorticoid-responsive element, GR, and glucocorticoids. [less ▲]

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See detailDNase I hypersensitive sites far upstream of the rat tryptophan oxygenase gene direct developmentally regulated transcription in livers of transgenic mice.
Kaltschmidt, Christian; Muller, Marc ULg; Brem, Gottfried et al

in Mechanisms of Development (1994), 45(3), 203-10

Expression of the gene coding for tryptophan oxygenase (TO) is switched on in rat liver about two weeks after birth. We identified two clusters of DNaseI hypersensitive (HS) sites in the TO gene upstream ... [more ▼]

Expression of the gene coding for tryptophan oxygenase (TO) is switched on in rat liver about two weeks after birth. We identified two clusters of DNaseI hypersensitive (HS) sites in the TO gene upstream region; one near the promoter, the other at a distant upstream location (-8.5 kb). Hypersensitivity of upstream sites was present in adult and in 7 day old rat liver, but absent in kidney. To investigate their role in transcriptional regulation, a reporter gene controlled by both HS site regions was used to generate transgenic mice. In these animals the transgene followed the cell specific and developmental regulation of the endogenous gene: inactive after birth and active in adult liver. Transgenes containing only the promoter proximal HS site were non-functional. [less ▲]

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See detailA complex composed of at least two HeLa nuclear proteins protects preferentially one DNA strand of the simple (gt)n(ga)m containing region of intron 2 in HLA-DRB genes.
Maueler, Winfried; Frank, G.; Muller, Marc ULg et al

in Journal of Cellular Biochemistry (1994), 56(1), 74-85

Electrophoretic mobility shift assays reveal that HeLa nuclear proteins bind fast and with measurable affinity to target DNAs containing mixed simple repetitive (gt)n(ga)m stretches. Preincubation of the ... [more ▼]

Electrophoretic mobility shift assays reveal that HeLa nuclear proteins bind fast and with measurable affinity to target DNAs containing mixed simple repetitive (gt)n(ga)m stretches. Preincubation of the proteins at elevated temperature prevents the formation of the major DNA/protein complex in favour of several distinct assemblies. A similar pattern of retarded bands was observed employing higher salt concentrations in the binding reaction. Thus conformational changes of different proteins appear to influence the complex rather than alternating DNA structures. Separation of the total nuclear extract into a water soluble and an insoluble protein fraction leads to a complete loss of target DNA binding capability of the fractions. The binding capacity is restored by combining the two fractions suggesting that at least two protein components are necessary to form a complex with the target sequence. The proteins can be differentiated into heat sensitive, water soluble and temperature stable, water insoluble, respectively. Furthermore, specifically binding polypeptides are not detectable by Southwestern analyses, probably because the essential components are separated during electrophoresis. DNase I footprint analyses yield four different protein binding regions only on the (gt)n(ga)m harbouring strand. The footprints cover larger portions of the mixed simple repeat in addition to a portion 5' of the (gt)n part. Hence at least two nuclear protein components of unknown biological function have to be present simultaneously to protect preferentially the (gt)n(ga)m-containing strand of intron 2 in HLA-DRB genes. [less ▲]

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See detailA gel retardation assay system for studying protein binding to simple repetitive DNA sequences.
Maueler, W.; Muller, Marc ULg; Kohne, A. C. et al

in Electrophoresis (1992), 13(1-2), 7-10

Simple repetitive DNA sequences have been regarded as mere "junk" present in all eukaryotic genomes. In fact, mixed simple repeat (gt)n(ga)m sequences are present in major histocompatibility complex MHC ... [more ▼]

Simple repetitive DNA sequences have been regarded as mere "junk" present in all eukaryotic genomes. In fact, mixed simple repeat (gt)n(ga)m sequences are present in major histocompatibility complex MHC-DRB genes for long evolutionary times, including such distant animals as artiodactyla and man. We describe herein an unsophisticated method which reveals that at least certain simple repetitive (gt)n(ga)m sequences bind nuclear proteins and show characteristics of a specific DNA-protein interaction via gel retardation. [less ▲]

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See detailCo-operative transactivation of steroid receptors
Muller, Marc ULg; Baniahmad, Claudia; Kaltschmidt, Christian et al

in Parker, Malcolm (Ed.) Nuclear Hormone Receptors (1991)

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See detailThe glucocorticoid receptor.
Muller, Marc ULg; Renkawitz, R.

in Biochimica et Biophysica Acta (1991), 1088

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See detailMultiple domains of the glucocorticoid receptor involved in synergism with the CACCC box factor(s).
Muller, Marc ULg; Baniahmad, C.; Kaltschmidt, C. et al

in Molecular Endocrinology (Baltimore, Md.) (1991), 5(10), 1498-503

Steroid induction of responsive genes functions through the synergistic activity of steroid receptor-binding sequences with adjacent transcription factor-binding sites. To analyze the mechanism of synergy ... [more ▼]

Steroid induction of responsive genes functions through the synergistic activity of steroid receptor-binding sequences with adjacent transcription factor-binding sites. To analyze the mechanism of synergy we tested different human glucocorticoid receptor mutants for synergistic function with another transcription factor in comparison with intrinsic trans-activation obtained with a single receptor binding site (glucocorticoid response element). Multiple domains were found to be involved in synergistic activity of the glucocorticoid receptor with the CACCC box factor. Deletions within the N-terminal receptor half affected simultaneously intrinsic trans-activation and synergism. However, deletion of the hormone-binding domain mainly impaired synergism rather than intrinsic trans-activation, clearly showing that this domain synergizes by a mechanism independent of intrinsic activation. A chimeric protein where the DNA-binding domain of the glucocorticoid receptor was replaced by that of the yeast GAL4 protein also showed functional synergism. These data suggest that some of the receptor domains outside the DNA-binding domain synergize by their intrinsic trans-activating property, but the hormone-binding domain contributes to synergism by a different mechanism. [less ▲]

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See detailCo-operative binding of the glucocorticoid receptor DNA binding domain is one of at least two mechanisms for synergism.
Baniahmad, Claudia; Muller, Marc ULg; Altschmied, Joachim et al

in Journal of Molecular Biology (1991), 222(2), 155-65

Steroid induction of responsive genes functions through the synergistic activity of steroid receptor binding sequences with adjacent binding sites either for other transcription factors or for further ... [more ▼]

Steroid induction of responsive genes functions through the synergistic activity of steroid receptor binding sequences with adjacent binding sites either for other transcription factors or for further steroid receptors. Analysis of the human glucocorticoid receptor revealed that the DNA-binding domain of the receptor is sufficient to mediate co-operative binding to adjacent receptor binding sites. This is a novel feature of the domain in addition to its DNA-binding, trans-activating and trans-repressing properties. Chimaeric proteins containing the N- or C-terminal receptor halves fused to the GAL4 DNA-binding domain do not co-operate in DNA-binding, however they do functionally synergize. Thus, at least two mechanisms contribute to the synergism of the human glucocorticoid receptor bound to two adjacent receptor binding sites. [less ▲]

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See detailCooperative interaction of chicken lysozyme enhancer sub-domains partially overlapping with a steroid receptor binding site.
Altschmied, J.; Muller, Marc ULg; Baniahmad, A. et al

in Nucleic Acids Research (1989), 17(13), 4975-91

Expression of the lysozyme gene is a marker for the differentiation of macrophages, lysozyme transcription being gradually increased during maturation. We have analyzed the fine structure and function of ... [more ▼]

Expression of the lysozyme gene is a marker for the differentiation of macrophages, lysozyme transcription being gradually increased during maturation. We have analyzed the fine structure and function of two macrophage-specific enhancer elements of the chicken lysozyme gene (E-2.7 kb and E-0.2 kb). Both increase their activities upon LPS induction, both contain multiple binding sites for similar or identical nuclear factors and both can be divided into two functional modules. For the E-0.2 kb enhancer we found a synergistic activity of the modules to be dependent on their distance. Binding sites for nuclear proteins within enhancer E-0.2 kb overlap substantially with the previously identified progesterone/glucocorticoid receptor binding site, which is required for steroid induction of lysozyme transcription in the oviduct. [less ▲]

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See detailPairing Properties of Bromouracil and Repair of Bromouracil-Containing DNA. Possible Utilization of Bromodeoxyuridine Triphosphate for Site-Directed Mutagenesis
Muller, Marc ULg; Martial, Joseph ULg; Verly, W. G.

in Biochemical Journal (1988), 253(3), 637-643

5-Bromo-2'-deoxyuridine triphosphate (Br-dUTP) and dTTP are used interchangeably for DNA synthesis in vitro by the Klenow fragment of Escherichia coli DNA polymerase I. When DNA containing Br-dUMP instead ... [more ▼]

5-Bromo-2'-deoxyuridine triphosphate (Br-dUTP) and dTTP are used interchangeably for DNA synthesis in vitro by the Klenow fragment of Escherichia coli DNA polymerase I. When DNA containing Br-dUMP instead of dTMP at a few preselected sites is transfected into competent bacteria, no mutation occurs, indicating that in vivo E. coli DNA polymerase always places a dAMP residue in front of any unrepaired Br-dUMP residue. On the other hand, in vitro Br-dUTP can also replace dCTP, but only with difficulty: when dCTP is absent, Br-dUMP can be forced in front of a dGMP residue, but the Klenow polymerase pauses before and after addition of Br-dUMP. Transfection into E. coli of the substituted DNA leads to the expected G----A transitions. These mutations can easily be targeted by using a suitable primer and the correctly chosen mix of deoxynucleoside triphosphates containing Br-dUTP. When Br-dUMP has been placed in front of a dGMP residue, the mutation yield is not 100%, showing a partial repair of the transfected DNA before it is replicated. Advantage can be taken of this partial repair to prepare a set of different mutations within a target region in a single experiment. [less ▲]

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See detailMany transcription factors interact synergistically with steroid receptors.
Schule, Roland; Muller, Marc ULg; Kaltschmidt, Christian et al

in Science (1988), 242(4884), 1418-20

Progesterone (PRE) or glucocorticoid receptor (GRE) DNA binding sites are often found clustered with binding sites for other transcription factors. Individual protein binding sites were tested without the ... [more ▼]

Progesterone (PRE) or glucocorticoid receptor (GRE) DNA binding sites are often found clustered with binding sites for other transcription factors. Individual protein binding sites were tested without the influence of adjacent factors by analyzing isolated combinations of several transcription factor binding sites with PREs or GREs. All show strong synergistic effects on steroid induction. The degree of synergism is inversely related to the strength of the GRE. Thus, a steroid responsive unit can be composed of several modules that, if positioned correctly, act synergistically. [less ▲]

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See detailCooperativity of the glucocorticoid receptor and the CACCC-box binding factor.
Schule, Roland; Muller, Marc ULg; Otsuka-Murakami, Hidetsuka et al

in Nature (1988), 332(6159), 87-90

Glucocorticoid receptor binding sites (GRE) are often tightly clustered with other transcription factor binding sequences. Examples of this occur upstream of the genes for chicken lysozyme and human ... [more ▼]

Glucocorticoid receptor binding sites (GRE) are often tightly clustered with other transcription factor binding sequences. Examples of this occur upstream of the genes for chicken lysozyme and human metallothionein IIA (ref. 3), in several retroviral LTRs and upstream of the rat tryptophan oxygenase (TO) gene. In the TO gene, sequences immediately upstream of a glucocorticoid receptor binding site are required for steroid induction and contain a CACCC-box identical to that found in the beta globin gene. Here we demonstrate specific binding to this TO-CACCC element and show that it will also act cooperatively with a MMTV glucocorticoid receptor binding site. The response to dexamethasone is independent of the order and relative orientation of these elements but does depend on their precise spacing. Optimal induction occurs at a periodicity of approximately 10 base pairs (bp) indicating a requirement for stereospecific alignment. Binding to the CACCC box, however, is not affected by its distance from the glucocorticoid receptor site. We conclude that the observed cooperativity is mediated by protein:protein interactions and does not depend on cooperative DNA binding. [less ▲]

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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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