Differential gene activation by glucocorticoids and progestins through the hormone regulatory element of mouse mammary tumor virus

Chalepakis, Georges; Arnemann, J.; Slater, Emily P.; Brüller, Hans-Joachim; Gross, B.; Beato, Miguel

doi:10.1016/0092-8674(88)90157-2

Cited by 204 publications

(130 citation statements)

References 29 publications

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“…For example, in the lysis/lysogeny switch of bacteriophage λ, cro and repressor compete for related sites in the rightward operator 28 . In eukaryotes, a number of regulatory proteins have been shown to be members of protein families with related DNA-binding specificities [29][30][31][32][33][34][35][36][37] . In fact, a member of the nuclear hormone receptor family, thyroid hormone receptor, was recently shown to mediate negative effects on transcription from oestrogen-responsive DNA elements, apparently by competing with oestrogen receptor for binding to the elements 38 .…”

Section: Discussionmentioning

confidence: 99%

Activation and repression of transcription by homoeodomain-containing proteins that bind a common site

Jaynes

O’Farrell

1988

Nature

223

148

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The product of the fushi tarazu (ftz) gene is shown to be a site-dependent activator of transcription. In vitro-defined binding sites act as ftz-dependent enhancers in cultured cells. Another homoeodomain-containing protein, the engrailed gene product, competes for homoeodomainbinding sites and counteracts ftz activation.GENETIC analysis in Drosophila melanogaster has identified a group of regulatory genes that participate in embryonic pattern formation 1,2 . Many of these genes encode a 60 amino-acid sequence, the homoeodomain, that is highly conserved through evolution [3][4][5] . This domain contains a putative helix-turn-helix motif 6 such as that found in a number of bacterial regulators 7 , and possesses a sequence-specific DNA-binding activity 8,9 . Numerous regulatory interactions occur among homoeodomain-encoding genes during development. For example, a combination of segmentation and homoeotic gene products, many of which contain homoeodomains 1 , specify the developmental fates of cells in striped patterns 10,11 . Furthermore, homoeodomain-containing proteins (homoeodomain proteins) regulate both each other 12 and downstream (`cytodifferentiation' 13 ) genes. Consequently, it has been attractive to think of homoeodomain proteins as direct regulators of transcription. Due to the complexity of cross-regulatory interactions however, mutations altering or eliminating one homoeodomain protein generally change the expression patterns of many other regulators, confounding efforts to distinguish direct from indirect regulation. Additionally, suspected target genes contain large cis-acting control regions that respond, directly or indirectly, to complex combinations of regulators [14][15][16][17] . As a result, identification of target genes directly regulated by homoeodomain proteins has been problematic.Previous studies have documented instances in which homoeodomain proteins control transcription. The enhancer activity of a DNA fragment from the ftz gene, a homoeodomaincontaining member of the pair-rule class of segmentation genes, suggested that the ftz gene product (ftz) activates its own expression in the embryo 18 . In a different approach a Drosophila tissue culture system was used to show that the Ultrabithorax (Ubx) gene product induces expression of its own promoter, and inhibits the Antennapedia (Antp) (P1) promoter (M. Krasnow and D. S. Hogness, personal communication, see ref. 19 for summary). In these cases however, the complexity of the regulatory circuitry and of the responding control regions leaves open the possibility that the homoeodomain proteins produce these transcriptional effects through intermediaries. To circumvent the complexities of natural target genes, we chose to use binding sites identified in vitro to build homoeodomain-responsive promoters. We find that ftz is a potent activator of transcription from these promoters in cultured cells.During sequential subdivision of the Drosophila embryo to produce segmentally repeating patterns, combinations of regulatory gene prod...

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Section: Discussionmentioning

confidence: 99%

Activation and repression of transcription by homoeodomain-containing proteins that bind a common site

Jaynes

O’Farrell

1988

Nature

223

148

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“…Preparation of NRE1 DNA Affinity Matrices-To prepare a singlestranded DNA oligonucleotide affinity column for the purification of proteins binding to the upper strand of NRE1 (upNRE1), an 80-mer oligonucleotide containing four copies of the upNRE1 sequence 5Ј-(ACT-GAGAAAGAGAAAGACGA) 4 -3Ј was synthesized on a Beckman Oligo 1000 DNA synthesizer. This oligonucleotide was coupled to cyanogen bromide-activated Sepharose CL-2B as described previously (52,53).…”

Section: Methodsmentioning

confidence: 99%

“…The identity of these factors and their role in NRE1-mediated transcriptional regulation is not known. The potential for these strand-specific factors to interact with NRE1 in vivo is particularly intriguing in light of the helicase activity of Ku (46) and our previous observation that nuclear factor binding to double-stranded NRE1 induces Mg 2ϩ -dependent structural transitions in MMTV LTR flanking sequences that are sensitive to the single strand-specific agents, KMnO 4 and S1 nuclease (50).…”

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confidence: 99%

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Sequence-specific Binding of Ku Autoantigen to Single-stranded DNA

Torrance¹,

Giffin²,

Rodda³

et al. 1998

Journal of Biological Chemistry

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Glucocorticoid-induced transcription of mouse mammary tumor virus is repressed by Ku antigen/DNA-dependent protein kinase (DNA-PK) through a DNA sequence element (NRE1) in the viral long terminal repeat. Nuclear factors binding to the separated single strands of NRE1 have been identified that may also be important for transcriptional regulation through this element. We report the separation of the upper-stranded NRE1 binding activity in Jurkat T cell nuclear extracts into two components. One component was identified as Ku antigen. The DNA sequence preference for Ku binding to single-stranded DNA closely paralleled the sequence requirements of Ku for double-stranded DNA. Recombinant Ku bound the single, upper strand of NRE1 with an affinity that was 3-4-fold lower than its affinity for double-stranded NRE1. Sequence-specific single-stranded Ku binding occurred rapidly (t1 ⁄2 on ‫؍‬ 2.0 min) and was exceptionally stable, with an off rate of t1 ⁄2 ‫؍‬ 68 min. While Ku70 cross-linked to the upper strand of NRE1 when Ku was bound to double-stranded and single-stranded DNAs, the Ku80 subunit only crosslinked to single-stranded NRE1. Intriguingly, addition of Mg 2؉ and ATP, the cofactors required for Ku helicase activity, induced the cross-linking of Ku80 to a doublestranded NRE1-containing oligonucleotide, without completely unwinding the two strands.Mouse mammary tumor virus is a slow transforming retrovirus that causes mammary tumors in lactating mice (1, 2). Transcription of MMTV 1 is strongly induced by steroid hormones through a promoter proximal regulatory region of the LTR that has been characterized in great detail (3-10). A second region, at the 5Ј end of the LTR, mediates tissue-specific expression and responsiveness to prolactin (11,12). Recently, it has been demonstrated that the region of the viral LTR between Ϫ420 and Ϫ360 contains sequences that act to repress viral transcription in several cell types, but most notably in T cells (13)(14)(15)(16)(17)(18)(19)(20). These sequences appear to be important for restricting cellular transformation by MMTV to the mammary gland, as viruses containing deletions encompassing this region of the LTR induce T cell lymphoma in addition to mammary carcinoma (19,(21)(22)(23)(24)(25)(26).In preliminary mapping experiments, we identified a 14-base pair polypurine/polypyrimidine DNA sequence element (NRE1) within the negative regulatory region of the LTR of the GR strain of MMTV that was sufficient to repress glucocorticoid hormone-induced MMTV transcription (20). Subsequently, we demonstrated that this sequence functioned as a direct, sequence-specific DNA binding site for Ku autoantigen/ DNA-dependent protein kinase (DNA-PK) (27). Both Ku and the DNA-PK catalytic subunit (DNA-PK cs ) were found to be required for the transcriptional effects of NRE1 on MMTV expression (27).Ku (p70/p80) is an unusual DNA-binding protein that functions as both a DNA binding subunit and an allosteric activator of the DNA-PK cs (28). Ku/DNA-PK cs are predominantly nuclear proteins that are in...

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“…While a simple HRE mediates induction in transfection by several receptors (13,38), enhancers of GR-responsive genes are often composed of multiple imperfect consensus elements or halfelements (5,17,18 (32,39). Fewer AR-responsive genes have been described, but they face a greater challenge for specific expression, because in most AR target organs GR is also present and at much higher levels.…”

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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.

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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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Differential gene activation by glucocorticoids and progestins through the hormone regulatory element of mouse mammary tumor virus

Cited by 204 publications

References 29 publications

Activation and repression of transcription by homoeodomain-containing proteins that bind a common site

Activation and repression of transcription by homoeodomain-containing proteins that bind a common site

Sequence-specific Binding of Ku Autoantigen to Single-stranded DNA

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

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