A Steroid Response Element Can Function in the Absence of a Distal Promoter

Bradshaw, Michael S.; Tsai, Ming‐Jer; O’Malley, Bert W.

doi:10.1210/mend-2-12-1286

Cited by 23 publications

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“…As has been shown for the simian virus 40 enhancer, multimerization of enhancer elements that appear only once in the wild-type enhancer reconstitutes an active enhancer (references 7 and 16 and references therein). Similarly, duplication of the steroid hormone-responsive elements can eliminate the requirement of other cis-acting elements in stimulating transcription from the TATA box (2). Our LS mutagenesis result indicates that at least seven sequence elements are important for rInSII expression.…”

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confidence: 62%

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Cooperativity of sequence elements mediates tissue specificity of the rat insulin II gene.

Hwung

Tsai

1990

Mol. Cell. Biol.

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The 5'-flanking region of the rat insulin II gene (-448 to +50) is sufficient for tissue-specific expression. To further determine the tissue-specific cis-acting element(s), important sequences defined by linker-scanning mutagenesis were placed upstream of a heterologous promoter and transfected into insulin-producing and -nonproducing cells. Rat insulin promoter element 3 (RIPE3), which spans from -125 to -86, was shown to confer jI-cell-specific expression in either orientation. However, two subregions of RIPE3, RIPE3a and RIPE3b (defined by linker-scanning mutations), displayed only marginal activities. These results suggest that the two subregions cooperate to confer tissue specificity, presumably via their cognate binding factors.The insulin gene is expressed exclusively in pancreatic I cells in normal adults and is therefore a good model system for the study of tissue-specific gene expression. Previous studies have shown that less than 600 base pairs (bp) of the 5'-flanking sequences are sufficient for tissue specificity of the insulin gene in both cultured cells (6, 23) and transgenic mice (10). Therefore, the interaction between upstream sequence elements and trans-acting factors is important for regulation of insulin gene expression. Upstream flanking sequences of the mammalian insulin genes are homologous up to 500 bp (22). Furthermore, interspecies gene transfer experiments indicate that the molecular mechanism underlying the tissue specificity of the insulin gene is conserved among mammals.There are two nonallelic insulin genes in rats, the rat insulin I (rInsI) and rat insulin II (rInsII) genes (3, 23). These two genes have more than 80% sequence similarity in both the coding and flanking sequences, and they are coordinately expressed (8). The rInslI gene is more similar in structure than the rInsI gene to the other mammalian insulin genes, and it is proposed that rlnsl gene was duplicated from the ancestral rInsIl gene (21). To better define which sequences within the 5'-flanking region of the rInsIl gene are important for gene activity, linker-scanning (LS) mutagenesis was carried out in our laboratory (4). Mutation of seven regions (referred to as the rat insulin promoter elements [RIPEs]) resulted in significant decreases in gene activity, suggesting that the insulin gene control region is composed of several functional domains or cis elements. These cis elements may cooperate through their cognate trans-acting factors to achieve high levels of transcription. One of the trans-acting factor is the COUP (chicken ovalbumin upstream promoter) transcription factor (18,19), which binds to RIPE1 (-53 to -46) and is likely to play an important role in insulin promoter function (11). Interestingly, the COUP transcription factor contacts the insulin and ovalbumin promoter quite differently (12), the physiological significance of which remains unknown.These mutagenesis results, however, did not define the control element(s) for tissue specificity. It is possible that one or a combination of the LS-define...

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confidence: 62%

“…As expected, the wild-type insulin plasmid did not display any CAT activity. were observed in CV-1 and M6 cells (data not shown; see reference 2). Therefore, the ovalbumin gene minimal promoter can function in non-insulin-producing cells, and the tissue specificity of the RIPE3-pOVCAT-50 construct is derived from RIPE3.…”

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confidence: 87%

Cooperativity of sequence elements mediates tissue specificity of the rat insulin II gene.

Hwung

Tsai

1990

Mol. Cell. Biol.

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“…We chose the TAT GRE sequences because the PEPCK GREs have a noncanonical sequence and can drive transcription only weakly in the absence of their adjacent accessory factor sites (20). The TAT GREs, which differ from the consensus GRE sequence by only one base, can act as independent transcriptional enhancers (21). This construct responded to Dex induction in a dose-dependent manner that was similar to that of the PEPCK-Luc construct (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

Arsenic alters the function of the glucocorticoid receptor as a transcription factor.

Kaltreider

Davis

Lariviere

et al. 2001

Environ Health Perspect

228

131

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Chronic human exposure to nonovertly toxic doses of arsenic is associated with an increased risk of cancer. Although its carcinogenic mechanism is still unknown, arsenic does not directly cause DNA damage or mutations and is therefore thought to act principally as a co-mutagen, co-carcinogen, and/or tumor promoter. Previous studies in our laboratory demonstrated that effects of low-dose arsenic (III) (arsenite) on expression of the hormone-regulated phosphoenolpyruvate carboxykinase (PEPCK) gene were strongly associated with the glucocorticoid receptor (GR)-mediated regulatory pathway. We therefore examined specifically the effects of arsenite on the biochemical function of GR in hormone-responsive H4IIE rat hepatoma cells. Completely noncytotoxic arsenite treatments (0.3-3.3 microM) significantly decreased dexamethasone-induced expression of transiently transfected luciferase constructs containing either an intact hormone-responsive promoter from the mammalian PEPCK gene or two tandem glucocorticoid response elements (GRE). Western blotting and confocal microscopy of a green fluorescent protein-tagged-GR fusion protein demonstrated that arsenite pretreatment did not block the normal dexamethasone-induced nuclear translocation of GR. These data indicate that nontoxic doses of arsenite can interact directly with GR complexes and selectively inhibit GR-mediated transcription, which is associated with altered nuclear function rather than a decrease in hormone-induced GR activation or nuclear translocation.

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“…YY1-binding activity, on the other hand, is not appreciably affected by the transfection, thus separating the down-regulation of YY1 observed during myogenesis from the up-regulation of SRF. (12 ,ug), TKCAT (3 ,g), and SV2CAT (3 ,ug) were as described (20,25). Plasmid pTC21, the parental SRF expression vector, was used to adjust the expression vector DNA concentration to 5 A&g. Normalized CAT activities (6) obtained in the absence of pMSV-SRF were arbitrarily set at 1.…”

Section: Resultsmentioning

confidence: 99%

Displacement of BrdUrd-induced YY1 by serum response factor activates skeletal alpha-actin transcription in embryonic myoblasts.

Lee

Shi

Schwartz

1992

Proc. Natl. Acad. Sci. U.S.A.

201

129

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Muscle-restricted transcription ofthe skeletal a-actin gene is controlled in part by a positive regulator, serum response factor (SRF), and a negative regulator, F-ACT1, which bind competitively to the most proximal serum response element (SRE1). We show here that F-ACTl is identical to a transcription factor recently cloned and described as YY1, NF-E1, 8, or UCRBP. We found that although the DNAbinding activity of SRF accumulates during myogenesis, that of YY1 diminishes simultaneously. Myoblasts rendered incapable of differentiation by BrdUrd treatment exhibited the highest level of YY1 and the lowest level of SRF activities. Transfected SRF could directly transactivate the skeletal a-actin promoter by overcoming the inhibitory effect of BrdUrd-induced YYl. The transactivation depends on intact SRE DNA elements and requires the DNA-binding/dimerization domain of SRF as well as its C-terminal half rich in serines and threonines. Since the functions of YY1 and SRF appear to be developmentally regulated, the convergence of their binding sites upon the SRE constitutes an integrated mechanism whereby temporal and spatial muscle gene expression may be accomplished.

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A Steroid Response Element Can Function in the Absence of a Distal Promoter

Cited by 23 publications

References 0 publications

Cooperativity of sequence elements mediates tissue specificity of the rat insulin II gene.

Cooperativity of sequence elements mediates tissue specificity of the rat insulin II gene.

Arsenic alters the function of the glucocorticoid receptor as a transcription factor.

Displacement of BrdUrd-induced YY1 by serum response factor activates skeletal alpha-actin transcription in embryonic myoblasts.

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