Negative Regulation by Glucocorticoids Through Interference with a cAMP Responsive Enhancer

Akerblom, Ingrid; Slater, Emily P.; Beato, Miguel; Baxter, John D.; Mellon, Pamela L.

doi:10.1126/science.2838908

Cited by 492 publications

(160 citation statements)

References 32 publications

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“…There have been several mechanisms by which GR-mediated transrepression. These include that GR binds to sequences overlapping a cis-acting element for another trans-acting factor, thereby displaces it from, or prevents its binding to the cognate element (Akerblom et al, 1988;Drouin et al, 1989;Oro et al, 1988;StroÈ mstedt et al, 1991). GR-mediated transrepression has also been attributed to the direct or indirect interaction of the GR with other transacting factors, resulting in inhibition of their activity and/or ability to bind to DNA (Celada et al, 1993;Diamond et al, 1990;Gauthier et al, 1993;Jonat et al, 1990;Kutoh et al, 1992;Lucibello et al, 1990;Ray and Prefontaine, 1994;SchuÈ le et al, 1990;Tverberg and Russo, 1992;Yang-Yen et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

Ursolic acid-induced down-regulation of MMP-9 gene is mediated through the nuclear translocation of glucocorticoid receptor in HT1080 human fibrosarcoma cells

et al. 1998

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We have previously reported that ursolic acid, a pentacyclic triterpene acid, inhibited the invasion of HT1080 human ®brosarcoma cells by reducing the expression of matrix metalloproteinase-9. Since the chemical structure of ursolic acid is very similar to that of dexamethasone, a synthetic glucocorticoid, we investigated whether ursolic acid acts through the glucocorticoid receptor. The expression of matrix metalloproteinase-9 is thought to be regulated similarly with matrix metalloproteinase-1 and matrix metalloproteinase-3 as containing common 2-O-tetradecanoylphorbol-acetate responsible region, where AP-1 proteins can bind. Dexamethasone has been studied to repress the 2-O-tetradecanoylphorbolacetate-induced expression of matrix metalloproteinase-1 and matrix metalloproteinase-3 through a glucocorticoid receptor-mediated manner. In Northern blot analysis, we found that ursolic acid reduced the expression of matrix metalloproteinase-1 and matrix metalloproteinase-3 induced by 2-O-tetradecanoylphorbol-acetate. Similarly, ursolic acid down-regulated 2-O-tetradecanoylphorbolacetate-induction of matrix metalloproteinase-9 gene in the same manner of dexamethasone. RU486, a potent glucocorticoid receptor antagonist, was used for identifying that ursolic acid-induced down-regulation of matrix metalloproteinase-9 expression is mediated by its binding to glucocorticoid receptor. The e ect of ursolic acid on the matrix metalloproteinase-9 expression was blocked by RU486, suggesting that ursolic acid acts via a glucocorticoid receptor in the regulation of matrix metalloproteinase-9. Western blot analysis and immunocytochemistry showed that ursolic acid increased glucocorticoid receptor fraction in the nucleus, although it decreased the synthesis of glucocorticoid receptor mRNA. In addition, ursolic acid did not decrease the expression of c-jun and DNAbinding activity of AP-1 to its cognate sequences. Taken together, we suggest that ursolic acid may induce the repression of matrix metalloproteinase-9 by stimulating the nuclear translocation of glucocorticoid receptor, and the translocated glucocorticoid receptor probably downmodulating the trans-activating function of AP-1 to 2-Otetradecanoylphorbol-acetate responsible element of matrix metalloproteinase-9 promoter region.

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Section: Discussionmentioning

confidence: 99%

Ursolic acid-induced down-regulation of MMP-9 gene is mediated through the nuclear translocation of glucocorticoid receptor in HT1080 human fibrosarcoma cells

et al. 1998

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“…Several examples of steroid hormone-mediated repression suggest direct binding competition between inactive forms of the steroid hormones and positive-acting factors. Competition between an inactive form of the glucocorticoid receptor (GR) and activated CREB protein has been implicated in the control of the human glycoprotein hormone a-subunit gene (Akerblom et al 1988;Oro et al 1988). Stimulation of a Xenopus vitellogenin gene by estrogen receptor (ER) has been shown to be down-regulated by thyroid hormone receptor (TR) (Glass et al 1988).…”

Section: Role Of a Genetic Switch In Establishing Cell Type Specificitymentioning

confidence: 99%

Modulation of the IgH enhancer's cell type specificity through a genetic switch.

Ruezinsky¹,

Beckmann²,

Kadesch³

1991

Genes Dev.

100

103

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Using defined regions of the immunoglobulin heavy-chain enhancer linked to minimal promoters and cDNAs that encode the two helix-loop-helix transcription factors ITF-1 and TFE3, we demonstrate that activity of an otherwise repressed enhancer can be stimulated in nonlymphoid cells. Repression in non-B cells is mediated by the |JLE5 motif. Derepression occurs at two levels. First, overexpression of ITF-1, an E12/E47-telated protein that binds the |xE5 motif, leads to transcriptional activation itself. Second, binding of ITF-1 physically displaces a repressor that normally blocks the stimulatory activity of TFE3, which binds the neighboring |xE3 motif. TFE3 can only stimulate enhancer activity in the presence of ITF-1 or in the absence of a |xE5 motif. Hence, one component of the enhancer's cell type specificity can be artificially modulated through a "genetic switch" in which activity is dictated by the relative levels of ITF-1 and a competing repressor.[Key Words: Helix-loop-helix proteins; transcriptional activation; transcriptional repression; immunoglobulin enhancer; transcription factors ITF-1 and TFE3]

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“…There is also evidence of crosstalk between steroid receptor action and cyclic AMP (cAMP) signalling pathways. The glycoprotein hormone alpha-subunit gene provides an example of antagonism between activated CREB, a target of protein kinase A (PKA), and activated GR (2,61). Although there are overlapping sites for both transcription factors on the promoter, GR binding to DNA is not necessary for inhibition of transcription in response to activation of CREB (61).…”

mentioning

confidence: 99%

Nucleoprotein Structure Influences the Response of the Mouse Mammary Tumor Virus Promoter to Activation of the Cyclic AMP Signalling Pathway

Pennie

Hager

Smith

1995

Molecular and Cellular Biology

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Recent studies have provided evidence of crosstalk between steroid receptors and cyclic AMP (cAMP) signalling pathways in the regulation of gene expression. A synergism between intracellular phosphorylation inducers and either glucocorticoids or progestins has been shown to occur during activation of the mouse mammary tumor virus (MMTV) promoter. We have investigated the effect of 8-Br-cAMP and okadaic acid, modulators of cellular kinases and phosphatases, on the hormone-induced activation of the MMTV promoter in two forms: a transiently transfected template with a disorganized, accessible nucleoprotein structure and a stably replicating template with an ordered, inaccessible nucleoprotein structure. Both okadaic acid and 8-Br-cAMP synergize significantly with either glucocorticoids or progestins in activating the transiently transfected MMTV template. In contrast, 8-Br-cAMP, but not okadaic acid, is antagonistic to hormoneinduced activation of the stably replicating MMTV template. Nuclear run-on experiments demonstrate that this inhibition is a transcriptional effect on both hormone-induced transcription and basal transcription. Surprisingly, 8-Br-cAMP does not inhibit glucocorticoid-induced changes in restriction enzyme access and nuclear factor 1 binding. However, association of a complex with the TATA box region is inhibited in the presence of 8-Br-cAMP. Thus, cAMP treatment interferes with the initiation process but does not inhibit interaction of the receptor with the template. Since the replicated, ordered MMTV templates and the transfected, disorganized templates show opposite responses to 8-Br-cAMP treatment, we conclude that chromatin structure can influence the response of a promoter to activation of the cAMP signalling pathway.The mouse mammary tumor virus long terminal repeat (MMTV LTR) has been used extensively as a model for both steroid-induced transcription and the effects of chromatin structure on transcription. The MMTV promoter can be activated by glucocorticoids, progestins, androgens, and mineralocorticoids through their individual receptors (8,18,21,55). In chromatin, the MMTV LTR exists as an ordered array of six nucleosomes, one of which (Nuc-B) is associated with the promoter region containing binding sites for glucocorticoid receptor (GR) and nuclear factor 1 (NF1) (54). In the absence of activated GR, the MMTV chromatin template is found to be in a ''closed'' architecture, with the transcription factors NF1 and OTF1 largely occluded from their high-affinity binding sites (20,35). Upon treatment with glucocorticoids, the Nuc-B region undergoes a structural transition which results in an opening of chromatin structure, characterized by increased nuclease accessibility and the binding of NF1, OTF1, and the basal transcriptional machinery (4,20,35,54). These observations suggested a bimodal model of MMTV transcriptional activation (6), in which nucleoprotein structure limits the access of transcription factors to their sites on MMTV chromatin in the absence of hormone. This repression is ...

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Negative Regulation by Glucocorticoids Through Interference with a cAMP Responsive Enhancer

Cited by 492 publications

References 32 publications

Ursolic acid-induced down-regulation of MMP-9 gene is mediated through the nuclear translocation of glucocorticoid receptor in HT1080 human fibrosarcoma cells

Ursolic acid-induced down-regulation of MMP-9 gene is mediated through the nuclear translocation of glucocorticoid receptor in HT1080 human fibrosarcoma cells

Modulation of the IgH enhancer's cell type specificity through a genetic switch.

Nucleoprotein Structure Influences the Response of the Mouse Mammary Tumor Virus Promoter to Activation of the Cyclic AMP Signalling Pathway

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