Identification of a negative regulatory function for steroid receptors.

McDonnell, Donald P.; Vegeto, Elisabetta; O’Malley, Bert W.

doi:10.1073/pnas.89.22.10563

Cited by 88 publications

(48 citation statements)

References 26 publications

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“…An interesting activity of the SSN6 protein has been reported recently by McDonnell et al (1992). By use of a reconstituted estrogen-responsive transcription system in yeast, those investigators found that SSN6 acts as a repressor of transcription by the TAF1 domain of the estrogen receptor.…”

Section: Repression Of Other Genes By Ssn6 and Tupimentioning

confidence: 88%

“…By use of a reconstituted estrogen-responsive transcription system in yeast, those investigators found that SSN6 acts as a repressor of transcription by the TAF1 domain of the estrogen receptor. Although a model in which mutation of SSN6 leads to global alterations in chromatin structure was disfavored by McDonnell et al (1992), the possibility remains that such mutations lead to changes in the chromatin structures of a subset of genes to which the SSN6 protein is specifically recruited. Thus, if a m a m m a l i a n counterpart to the SSN6 protein exists, it will be worthwhile to investigate the possibility that such a protein acts in part via regulation of chromatin structure in m a m m a l i a n cells.…”

Section: Repression Of Other Genes By Ssn6 and Tupimentioning

confidence: 99%

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The global transcriptional regulators, SSN6 and TUP1, play distinct roles in the establishment of a repressive chromatin structure.

Cooper¹,

Roth²,

Simpson³

1994

Genes Dev.

184

161

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Repression of a-cell specific gene expression in yeast ~ cells requires MATch2 and MCM1, as well as two global repressors, SSN6 and TUP1. Previous studies demonstrated that nucleosomes positioned adjacent to the a2/MCM1 operator in c~ cells directly contribute to repression. To investigate the possibility that SSN6 and TUP1 provide a link between MAT~2/MCM1 and neighboring histones, nucleosome locations were examined in ssn6 and t u p l ot cells. In both cases, nucleosome positions downstream of the operator were disrupted, and the severity of the disruption correlated with the degree of derepression. Nevertheless, the observed changes in chromatin structure were not dependent on transcription. Our data strongly indicate that SSN6 and TUP1 directly organize repressive regions of chromatin.

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Section: Repression Of Other Genes By Ssn6 and Tupimentioning

confidence: 88%

Section: Repression Of Other Genes By Ssn6 and Tupimentioning

confidence: 99%

The global transcriptional regulators, SSN6 and TUP1, play distinct roles in the establishment of a repressive chromatin structure.

Cooper¹,

Roth²,

Simpson³

1994

Genes Dev.

184

161

View full text Add to dashboard Cite

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“…Transcription activation functions in general have been proposed to act as inhibitors (50), and reduced concentrations of SPT6, which is active in yeast and mammalian cells, caused a left shift in the estrogen dose-response curve (51). Genetic deletion of the yeast repressor SSN6 also caused increased percentages of agonist activity for antiestrogens, but not antiprogestins, and a Ն10-fold left shift in the dose-response curve for agonists bound to estrogen or progesterone receptors in yeast (52). Unfortunately, no mammalian homologues of SSN6 have yet been described.…”

Section: Discussionmentioning

confidence: 99%

Induction Properties of a Transiently Transfected Glucocorticoid-responsive Gene Vary with Glucocorticoid Receptor Concentration

Szapary

Simons

1996

Journal of Biological Chemistry

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Transient transfections of steroid receptors have yielded much of the data used to construct the current models of steroid hormone action. These experiments invariably examine the ability of receptors to regulate transcription when occupied by saturating concentrations of steroid. We now report that other induction properties of a transiently transfected gene are not constant but vary with the concentration of transiently transfected glucocorticoid receptors. Thus, the percentage of maximal induction seen with subsaturating concentrations of glucocorticoid could be dramatically increased, and an antiglucocorticoid could be converted into a partial glucocorticoid, simply by increasing the concentration of glucocorticoid receptors. This behavior was observed in HeLa cells, containing endogenous receptors, or in CV-1 cells, containing almost no endogenous receptor, with either homologous or heterologous receptors. These increases were relatively insensitive to the concentration of reporter gene, suggesting the titration of some transcription factor(s) involved in regulating the position of the glucocorticoid dose-response curve and the agonist activity of an antiglucocorticoid. This property of transfected glucocorticoid receptors required a full-length, functionally active receptor but was retained, albeit reduced in magnitude, in the absence of binding to a glucocorticoid response element. Furthermore, this phenomenon was specific in that the A form of the human progesterone receptor had no effect under the same conditions. These variations in induction properties of antiglucocorticoids and of subsaturating concentrations of glucocorticoid, in a manner that was proportional to the amount of transfected receptor, reveal processes that are not operative with saturating concentrations of glucocorticoid. These variations also demonstrate that caution should be exercised in making mechanistic conclusions based solely on experiments conducted with saturating concentrations of glucocorticoid.The overriding experimental advantage of transient transfections is time. Thus, the biological consequences of altered nucleotide compositions in the cDNAs encoding active proteins, and in genomic sequences, can be examined in a fraction of the time required to establish cell lines with the same sequences stably integrated into the cellular genome. In the field of steroid receptors, most of the recent advances have emerged from transient transfection experiments, including the contributions of cis-acting elements (1, 2), of different nucleotides in receptor binding to the hormone-responsive element (3), of various regions of receptors in steroid binding and biological activity (reviewed in Ref. 4), of promoter structure and cell type as determinants for the activity of antisteroid activity (5), and of overlapping signaling systems such as dopamine (6), epidermal growth factor (7), and protein kinase A inducers (8, 9). The utility of transient transfections has been further enhanced by the development of the "two-hybrid" (10, 11) and...

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“…In most cell and promoter contexts, the transcriptional activity of steroid hormone receptors appears to require the functional synergy between the amino and carboxyl termini of each individual receptor (6,39,40,46,53,57). This synergy occurs as a consequence of an agonist-dependent association between the amino and carboxyl AFs of ER␣ (31), the androgen receptor (5,14,27), and hPRA and hPRB, respectively (54).…”

Section: Discussionmentioning

confidence: 99%

The Opposing Transcriptional Activities of the Two Isoforms of the Human Progesterone Receptor Are Due to Differential Cofactor Binding

Giangrande

Kimbrel

Edwards

et al. 2000

Molecular and Cellular Biology

347

200

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The human progesterone receptor (PR) exists as two functionally distinct isoforms, hPRA and hPRB. hPRB functions as a transcriptional activator in most cell and promoter contexts, while hPRA is transcriptionally inactive and functions as a strong ligand-dependent transdominant repressor of steroid hormone receptor transcriptional activity. Although the precise mechanism of hPRA-mediated transrepression is not fully understood, an inhibitory domain (ID) within human PR, which is necessary for transrepression by hPRA, has been identified. Interestingly, although ID is present within both hPR isoforms, it is functionally active only in the context of hPRA, suggesting that the two receptors adopt distinct conformations within the cell which allow hPRA to interact with a set of cofactors that are different from those recognized by hPRB. In support of this hypothesis, we identified, using phage display technology, hPRA-selective peptides which differentially modulate hPRA and hPRB transcriptional activity. Furthermore, using a combination of in vitro and in vivo methodologies, we demonstrate that the two receptors exhibit different cofactor interactions. Specifically, it was determined that hPRA has a higher affinity for the corepressor SMRT than hPRB and that this interaction is facilitated by ID. Interestingly, inhibition of SMRT activity, by either a dominant negative mutant (C'SMRT) or histone deacetylase inhibitors, reverses hPRA-mediated transrepression but does not convert hPRA to a transcriptional activator. Together, these data indicate that the ability of hPRA to transrepress steroid hormone receptor transcriptional activity and its inability to activate progesterone-responsive promoters occur by distinct mechanisms. To this effect, we observed that hPRA, unlike hPRB, was unable to efficiently recruit the transcriptional coactivators GRIP1 and SRC-1 upon agonist binding. Thus, although both receptors contain sequences within their ligand-binding domains known to be required for coactivator binding, the ability of PR to interact with cofactors in a productive manner is regulated by sequences contained within the amino terminus of the receptors. We propose, therefore, that hPRA is transcriptionally inactive due to its inability to efficiently recruit coactivators. Furthermore, our experiments indicate that hPRA interacts efficiently with the corepressor SMRT and that this activity permits it to function as a transdominant repressor.

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Identification of a negative regulatory function for steroid receptors.

Cited by 88 publications

References 26 publications

The global transcriptional regulators, SSN6 and TUP1, play distinct roles in the establishment of a repressive chromatin structure.

The global transcriptional regulators, SSN6 and TUP1, play distinct roles in the establishment of a repressive chromatin structure.

Induction Properties of a Transiently Transfected Glucocorticoid-responsive Gene Vary with Glucocorticoid Receptor Concentration

The Opposing Transcriptional Activities of the Two Isoforms of the Human Progesterone Receptor Are Due to Differential Cofactor Binding

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