Factor-assisted DNA binding as a possible general mechanism for steroid receptors. Functional heterogeneity among activated receptor-steroid complexes

Cavanaugh, Alice H.; Simons, S. Stoney

doi:10.1016/0960-0760(94)90191-0

Cited by 15 publications

(5 citation statements)

References 58 publications

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“…[5J Classical epithelial aldosterone target tissues achieve selectivity for mineralocorticoids by the production of 11 ~-hydroxysteroid dehydrogenase, an enzyme that oxidatively inactivates glucocorticoids. [9] There is also increasing evidence for the existence of another glucocorticoid binding site[loJ and for receptor subtypes. protein kinases A and C. [8] Moreover, maximal DNA binding requires the presence of low molecular weight factors present in the nucleus and cytoplasm.…”

Section: Biological Targets Of Glucocorticoidsmentioning

confidence: 99%

Topical Glucocorticoids with Improved Risk-Benefit Ratio

1996

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Topical glucocorticoids for dermal application were introduced more than 40 years ago and revolutionised the treatment of inflammatory skin diseases. Today these drugs are frequently administered, although systemic and local adverse drug reactions, especially skin atrophy, are feared complications of their use. This literature review evaluates the present state of topical glucocorticoid therapy for inflammatory skin diseases. Several attempts have been made to increase the safety of topical glucocorticoid treatment. With respect to conventional compounds, new application schedules, as well as new vehicles, have been proposed. New derivatives have also been synthesized, forming the novel group of nonhalogenated double-ester-type glucocorticoids. Among these latter compounds, prednicarbate and 6-methyl-prednisolone aceponate have been characterised most thoroughly. According to in vivo studies, their anti-inflammatory activity is in the order of that of betamethasone valerate (a frequently used medium potency glucocorticoid, which is obtained by halogenation of the pregnane nucleus of the steroid molecule). Furthermore, these new congeners induce less skin atrophy than conventional glucocorticoids, as determined by in vivo and in vitro studies. Qualitative and quantitative assessment of the therapeutic and adverse effects of non-halogenated double-ester-type glucocorticoids suggests an increased benefit-to-risk ratio.

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Section: Biological Targets Of Glucocorticoidsmentioning

confidence: 99%

Topical Glucocorticoids with Improved Risk-Benefit Ratio

1996

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“…Studies have also described proteins that facilitate the binding of steroid receptor homodimers to palindromic HREs in vitro. For the most part, the protein(s) responsible for facilitating steroid receptor-DNA binding has not been identified and has been characterized as an enriched protein fraction or as an isolated protein of a specific molecular mass (9,11,14,30,37,41,51,56). We previously showed that mammalian-cell nuclear extracts contain a protein(s) that substantially increases the binding of human progesterone receptor (PR) to its target DNA in vitro (15).…”

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confidence: 99%

High-Mobility Group Chromatin Proteins 1 and 2 Functionally Interact with Steroid Hormone Receptors To Enhance Their DNA Binding In Vitro and Transcriptional Activity in Mammalian Cells

Boonyaratanakornkit

Melvin

Prendergast

et al. 1998

Molecular and Cellular Biology

316

234

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We previously reported that the chromatin high-mobility group protein 1 (HMG-1) enhances the sequencespecific DNA binding activity of progesterone receptor (PR) in vitro, thus providing the first evidence that HMG-1 may have a coregulatory role in steroid receptor-mediated gene transcription. Here we show that HMG-1 and the highly related HMG-2 stimulate DNA binding by other steroid receptors, including estrogen, androgen, and glucocorticoid receptors, but have no effect on DNA binding by several nonsteroid nuclear receptors, including retinoid acid receptor (RAR), retinoic X receptor (RXR), and vitamin D receptor (VDR). As highly purified recombinant full-length proteins, all steroid receptors tested exhibited weak binding affinity for their optimal palindromic hormone response elements (HREs), and the addition of purified HMG-1 or -2 substantially increased their affinity for HREs. Purified RAR, RXR, and VDR also exhibited little to no detectable binding to their cognate direct repeat HREs but, in contrast to results with steroid receptors, the addition of HMG-1 or HMG-2 had no stimulatory effect. Instead, the addition of purified RXR enhanced RAR and VDR DNA binding through a heterodimerization mechanism and HMG-1 or HMG-2 had no further effect on DNA binding by RXR-RAR or RXR-VDR heterodimers. HMG-1 and HMG-2 (HMG-1/-2) themselves do not bind to progesterone response elements, but in the presence of PR they were detected as part of an HMG-PR-DNA ternary complex. HMG-1/-2 can also interact transiently in vitro with PR in the absence of DNA; however, no direct protein interaction was detected with VDR. These results, taken together with the fact that PR can bend its target DNA and that HMG-1/-2 are non-sequence-specific DNA binding proteins that recognize DNA structure, suggest that HMG-1/-2 are recruited to the PR-DNA complex by the combined effect of transient protein interaction and DNA bending. In transient-transfection assays, coexpression of HMG-1 or HMG-2 increased PR-mediated transcription in mammalian cells by as much as 7-to 10-fold without altering the basal promoter activity of target reporter genes. This increase in PR-mediated gene activation by coexpression of HMG-1/-2 was observed in different cell types and with different target promoters, suggesting a generality to the functional interaction between HMG-1/-2 and PR in vivo. Cotransfection of HMG-1 also increased reporter gene activation mediated by other steroid receptors, including glucocorticoid and androgen receptors, but it had a minimal influence on VDR-dependent transcription in vivo. These results support the conclusion that HMG-1/-2 are coregulatory proteins that increase the DNA binding and transcriptional activity of the steroid hormone class of receptors but that do not functionally interact with certain nonsteroid classes of nuclear receptors.Steroid hormone receptors are members of a superfamily of ligand-dependent transcriptional activators which direct the expression of specific gene networks involved in regulating the differen...

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“…Glucocorticoid and androgen receptors require RAF 130 for optimal DNA binding (13); for the estrogen receptor hsp 70 and 48-and 45-kDa proteins increase the DNA association rate (12); and in the case of GR low molecular weight factors have been seen with a similar function (38). Such an activity was not seen with GR and GRIP 170.…”

Section: Discussionmentioning

confidence: 91%

A Fraction Enriched in a Novel Glucocorticoid Receptor-interacting Protein Stimulates Receptor-dependent Transcription in Vitro

Eggert

Möws

Tripier

et al. 1995

Journal of Biological Chemistry

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Glucocorticoids influence numerous cell functions by regulating gene activity. The glucocorticoid receptor (GR) is a ligand-activated transcription factor and, like any other transcription factor, does not modulate gene activity just by binding to DNA. Interaction with other proteins is probably required to enhance the establishment of a functional transcription initiation complex. To identify such proteins, we analyzed the in vitro interaction of the glucocorticoid receptor bound to a double glucocorticoid response element with nuclear proteins and describe here three interacting proteins with different molecular weights. One of them, which we named GRIP 170 (GR-interacting protein), was purified and microsequenced, and it turned out to be an unknown protein. When tested in a cell-free transcription assay, the fraction highly enriched for GRIP 170 does not influence basal promoter activity but does enhance GR induction.

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Factor-assisted DNA binding as a possible general mechanism for steroid receptors. Functional heterogeneity among activated receptor-steroid complexes

Cited by 15 publications

References 58 publications

Topical Glucocorticoids with Improved Risk-Benefit Ratio

Topical Glucocorticoids with Improved Risk-Benefit Ratio

High-Mobility Group Chromatin Proteins 1 and 2 Functionally Interact with Steroid Hormone Receptors To Enhance Their DNA Binding In Vitro and Transcriptional Activity in Mammalian Cells

A Fraction Enriched in a Novel Glucocorticoid Receptor-interacting Protein Stimulates Receptor-dependent Transcription in Vitro

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