Androgen-specific gene activation via a consensus glucocorticoid response element is determined by interaction with nonreceptor factors.

Adler, Adam J.; Danielsen, Mark; Robins, Diane M.

doi:10.1073/pnas.89.24.11660

Cited by 125 publications

(80 citation statements)

References 29 publications

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“…This fragment contains several sequences similar to HREs, but only the 3'-most element, HRE-3, matches a full consensus, confers hormonal response on a reporter gene independent of additional elements, and binds full-length AR protein in vitro (2). HRE-3, however, did not account for the specificity of androgen activation, as multiple copies of this sequence inserted before a tkCAT reporter gene conferred even greater response to GR than to AR, suggesting that other elements in C'A9 must be required to delimit induction (1). Further evidence for a crucial role in hormonal specificity of non-HRE sequences and their cognate nonreceptor factors was obtained by comparing C'A9 expression in different cell types.…”

Section: Resultsmentioning

confidence: 99%

“…The Slp enhancer, located within the proviral long terminal repeat, contains a near-perfect consensus HRE that is necessary but not sufficient for hormonal induction (2). Although multimers of this HRE can be activated by GR and PR as well as by AR, hormonal specificity is enforced by interactions with nonreceptor elements within the enhancer (1). GR can bind the HRE within the enhancer but is prevented from transactivating in that context; this selectivity depends on the amino terminus of the receptor.…”

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confidence: 99%

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The stringency and magnitude of androgen-specific gene activation are combinatorial functions of receptor and nonreceptor binding site sequences.

Adler¹,

Scheller²,

Robins³

1993

Mol. Cell. Biol.

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The mechanism by which specific hormonal regulation of gene expression is attained in vivo is a paradox in that several of the steroid receptors recognize the same DNA element in vitro. We have characterized a complex enhancer of the mouse sex-limited protein (Slp) gene that is activated exclusively by androgens but not by glucocorticoids in transfection. Potent androgen induction requires both the consensus hormone response element (HRE) and auxiliary elements residing within the 120-bp DNA fragment C'A9. Multiple nonreceptor factors are involved in androgen specificity, with respect to both the elevation of androgen receptor activity and the inactivity of glucocorticoid receptor (GR), since clustered base changes at any of several sites reduce or abolish androgen induction and do not increase glucocorticoid response. However, moving the HRE as little as 10 bases away from the rest of the enhancer allows GR to function, suggesting that GR is repressed by juxtaposition to particular factors within the androgen-specific complex. Surprisingly, some sequence variations of the HRE itself, within the context of C'A9, alter the stringency of specificity, as well as the magnitude, of hormonal response. These HRE sequence effects on expression correspond in a qualitative manner with receptor binding, i.e., GR shows a threefold difference in affinities for HREs amongst which androgen receptor does not discriminate. Altering the HRE orientation within the enhancer also affects hormonal stringency, increasing glucocorticoid but not androgen response. The effect of these subtle variations suggests that they alter receptor position with respect to other factors. Thus, protein-protein interactions that elicit specific gene regulation are established by the array of DNA elements in a complex enhancer and can be modulated by sequence variations within these elements that may influence selection of precise protein contacts.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

The stringency and magnitude of androgen-specific gene activation are combinatorial functions of receptor and nonreceptor binding site sequences.

Adler¹,

Scheller²,

Robins³

1993

Mol. Cell. Biol.

Self Cite

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“…Since these mechanisms may not be used by PR, GR, MR, and AR, it is assumed that their highly variable N-terminal regions are responsible for the cell-and steroid-specific regulation of target genes. In support of this notion, induction of mouse sex-limited protein gene (slp) expression has been shown to be mediated by the N-terminal region of murine AR, but not by that of GR (7).…”

mentioning

confidence: 80%

Interaction between the Amino- and Carboxyl-terminal Regions of the Rat Androgen Receptor Modulates Transcriptional Activity and Is Influenced by Nuclear Receptor Coactivators

Ikonen

Palvimo

Jänne

1997

Journal of Biological Chemistry

324

248

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Identical N-terminal deletions in the wild-type rat androgen receptor (rAR) and a constitutively active rAR (AR⌬641-902) devoid of the ligand-binding domain (LBD) resulted in dissimilar consequences in transcriptional activation: deletion of residues 149 -295 abolished wild-type AR activity, but did not influence that of AR⌬641-902. The activity of the N-terminal transactivation domain is thus controlled by the hormone-occupied LBD, suggesting that the N-and C-terminal regions of rAR communicate. Consistent with this idea, a strong androgen-dependent interaction between the N-terminal region and LBD was demonstrated in a mammalian two-hybrid system using GAL4 and VP16 fusion proteins. This interaction can be direct or indirect. Several nuclear receptor coactivators (CBP, F-SRC-1, SRC-1, and RIP140) that interact with other steroid receptors were tested as potential mediators of the Nand C-terminal interaction of rAR using the mammalian two-hybrid system. CBP or F-SRC-1 not only enhanced AR-mediated transactivation, but also facilitated the androgen-dependent interaction between the N-and Cterminal domains, implying that part of the coactivatordependent transcriptional activation occurs via this mechanism. In contrast, SRC-1, a coactivator for the progesterone receptor, inhibited both AR-mediated transactivation and interaction between the N and C termini. Recruitment of coregulators may involve AR domains other than the LBD, as F-SRC-1 and CBP enhanced, but SRC-1 repressed, the transcriptional activity of AR⌬641-902. Collectively, interplay between the N-terminal region and LBD of rAR results in the formation of a transactivation complex that includes coregulators and that is mandatory for optimal activation of androgen-induced promoters.

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“…Subtle alterations in sequence or position of the HRE, or inclusion of binding sites for other factors, can reduce specificity and permit GR function (13). A chimeric receptor that replaced the AR N terminus with that of GR activated simple HREs but not the androgen-specific enhancer, demonstrating importance of this region in selectivity (10). However, the N terminus of AR before the DBD and LBD of GR was not sufficient to activate the specific enhancer.…”

mentioning

confidence: 99%

“…For androgen-specific response, the enhancer of the mouse sex-limited protein (Slp) gene depends on a consensus HRE and multiple nonreceptor factor binding sites within a 120-bp DNA fragment (10). GR not only fails to activate this enhancer in transfection, but blocks AR activation, dependent upon an intact GR DBD.…”

mentioning

confidence: 99%

Multiple Receptor Domains Interact to Permit, or Restrict, Androgen-specific Gene Activation

Scheller

Hughes

Golden

et al. 1998

Journal of Biological Chemistry

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A critical problem within transcription factor families is how diverse regulatory programs are directed by highly related members. Androgen and glucocorticoid receptors (AR, GR) recognize a consensus DNA hormone response element (HRE), but they activate target genes with precise specificity, largely dependent on the promoter and cell context. We have assessed the role of different receptor domains in hormone-specific response by testing chimeras of AR and GR for their ability to activate the androgen-specific enhancer of the mouse sex-limited protein (Slp) gene. Although all of the mutant receptors activated simple HREs, only a few activated the androgen-specific element. One component shared by receptors functional on the AR-specific target was the AR DNA binding domain. Activation was not due to differential DNA affinity but rather to the AR DNA binding domain escaping suppression directed at the GR DNA binding domain in this enhancer context. A further mechanism increasing specific activation was cooperation of receptors at multiple and weak HREs, which was accentuated in the presence of both the AR N terminus and ligand binding domain. These domains together increased recognition of weak HREs, as demonstrated by in vitro DNase I footprinting and transactivation of mutant enhancers. Further, AR N-terminal subdomains reported to interact directly with the ligand binding domain relieved an inhibitory effect imposed by that domain. Therefore, functions intrinsic to AR augment steroid-specific gene activation, by evading negative regulation operating on the domains of other receptors and by enhancing cooperativity through intra-and inter-receptor domain interactions. These subtle distinctions in AR and GR behavior enforce transcriptional specificity established by the context of nonreceptor factors.

show abstract

Androgen-specific gene activation via a consensus glucocorticoid response element is determined by interaction with nonreceptor factors.

Cited by 125 publications

References 29 publications

The stringency and magnitude of androgen-specific gene activation are combinatorial functions of receptor and nonreceptor binding site sequences.

The stringency and magnitude of androgen-specific gene activation are combinatorial functions of receptor and nonreceptor binding site sequences.

Interaction between the Amino- and Carboxyl-terminal Regions of the Rat Androgen Receptor Modulates Transcriptional Activity and Is Influenced by Nuclear Receptor Coactivators

Multiple Receptor Domains Interact to Permit, or Restrict, Androgen-specific Gene Activation

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