Binding characteristics of the thyroid hormone receptor homo- and heterodimers to consensus AGGTCA repeat motifs.

Wahlström, Gunilla; Sjöberg, Maria; Andersson, Monika L.; Nordström, Kristina; Vennström, Björn

doi:10.1210/mend.6.7.1324417

Cited by 46 publications

(30 citation statements)

References 31 publications

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“…The resulting electrophoretograms were dried, visualized by autoradiography, and quantified by use of a Betascan analyzer. In the absence of RXRs, c-ErbA and v-ErbA generally produced both monomeric and dimeric complexes, probably due to the low cooperativity with which the c-Erb A␣ isoform forms homodimers (7). Perhaps as a consequence of this low cooperativity, the ratio of monomers to dimers formed by a given ErbA protein did not significantly vary from one response element to another ( Fig.…”

Section: Methodsmentioning

confidence: 94%

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DNA Recognition by Normal and Oncogenic Thyroid Hormone Receptors

Judelson

Privalsky

1996

Journal of Biological Chemistry

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The nuclear hormone receptors regulate target gene expression in response to hormones of extracellular origin. The DNA binding specificity of these receptors therefore plays the critical role of defining the precise repertoire of target genes that respond to a given hormone. We report here an analysis of the DNA binding specificity of the thyroid hormone receptor (c-ErbA protein) and that of an oncogenic derivative, the v-ErbA protein. These otherwise closely similar proteins exhibit quite divergent DNA sequence specificities at multiple positions within the DNA binding site. The thyroid hormone receptor (c-ErbA protein) exhibits a particularly broad DNA specificity, whereas the v-ErbA protein is comparatively quite specific. Intriguingly, these differences in DNA recognition largely map to an N-terminal receptor domain not traditionally implicated in DNA binding, and are further influenced by heterodimer formation with retinoid X receptors. We propose that the N terminus of nuclear hormone receptors plays an critical role in DNA recognition by altering the conformation of the receptor domains that make the actual base-specific contacts.The nuclear hormone receptors are a family of ligand-regulated transcription factors that mediate cellular responses to a broad range of small hydrophobic hormones (1-5). Members of the family include the steroid receptors, the retinoid acid receptors (RARs), 1 retinoid X receptors (RXRs), and the thyroid hormone receptors (T 3 Rs). Additional diversity is generated within individual receptor classes by the expression of multiple receptor isoforms; for example, T 3 Rs are encoded by two separate loci, ␣ and ␤ (3, 4). Despite this diversity, the different nuclear hormone receptors share a common mode of action, functioning by binding to specific DNA sequences and regulating expression of nearby target genes (1-4, 6, 7).The DNA recognition properties of each receptor play the critical role of defining the specific repertoire of target genes that respond to a given hormone. Most receptors bind to DNA as protein dimers, with each receptor molecule binding to a "half-site," a conserved 6 -8-nucleotide DNA sequence (7-11). Recognition of the sequence of each half-site has generally been believed to be mediated exclusively by a zinc-finger motif within the center of each receptor (Fig. 1) (12-14). Amino acids in the P-box helix within this zinc-finger motif make direct contact with bases in the major grove of the DNA half-site, and altering amino acids in the P-box can alter the half-site specificity of the receptor (14 -22). An additional ␣-helix, the A-box located at the C-terminal extreme of the zinc-finger motif, makes minor groove contacts with bases at the 5Ј end of the half-site (14, 23).Aberrant forms of nuclear hormone receptors are involved in several forms of cancer. The v-erbA oncogene, for example, is a mutated copy of the host cell gene (c-erbA) for T 3 R␣-1 (24, 25). V-ErbA has sustained a number of mutations relative to its T 3 R␣ progenitor (Fig. 1); as a result, v-ErbA...

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Section: Methodsmentioning

confidence: 94%

“…Most receptors bind to DNA as protein dimers, with each receptor molecule binding to a "half-site," a conserved 6 -8-nucleotide DNA sequence (7)(8)(9)(10)(11). Recognition of the sequence of each half-site has generally been believed to be mediated exclusively by a zinc-finger motif within the center of each receptor ( Fig.…”

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confidence: 99%

DNA Recognition by Normal and Oncogenic Thyroid Hormone Receptors

Judelson

Privalsky

1996

Journal of Biological Chemistry

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“…In contrast, members of the thyroid/retinoid receptor subfamily bind to structurally diverse HREs consisting of two or more hexanucleotide halfsites organized as inverted, everted, or direct repeats separated by different-size nucleotide gaps (20,26,27,44,78). This subfamily of receptors binds to these HREs as monomers and homodimers (9,20,61,66,79) or as heterodimers with the related retinoid X receptors (RXRs) (1,5,10,20,42,48,51,81,83).…”

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confidence: 99%

A 10-Amino-Acid Sequence in the N-Terminal A/B Domain of Thyroid Hormone Receptor α Is Essential for Transcriptional Activation and Interaction with the General Transcription Factor TFIIB

Hadzic

Desai-Yajnik

Helmer

et al. 1995

Molecular and Cellular Biology

109

111

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Transcription of eukaryotic protein-encoding genes by RNA polymerase II is modulated by two distinct classes of transcription factors. The first class comprises general transcription factors which are necessary for accurate initiation of transcription. These factors include TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIG/J, and TFIIH (11, 82). TFIID is a multiprotein complex consisting of TATA-binding protein (TBP) complexed with a number of TBP-associated factors (73). The binding of TFIID is thought to be the first step in transcriptional initiation (11, 82). The subsequent binding of TFIIB is thought to be involved in bringing RNA polymerase II to the complex through the association of TFIIF (34, 37). This leads to the recruitment of TFIIE and TFIIH and possibly other factors, which ultimately results in the initiation of transcription (11,75,82).The magnitude of transcriptional activity is greatly affected by the second class of transcription factors that generally bind to distal control DNA elements (52). These sequence-specific factors act to either promote or inhibit the formation of an active transcriptional initiation complex. Recent in vitro transcription studies suggest that the entry of TFIIB may be rate limiting for transcriptional initiation and that several transcriptional activators act to recruit or stabilize the interaction of TFIIB with the initiation complex (14, 62). TFIIB contains a potential N-terminal zinc finger structure (amino acids 14 to 36) that may be important for interaction with RNA polymerase II and TFIIF (34), a more C-terminal amphipathic ␣ helix (amino acids 184 to 201), and two imperfect repeats (amino acids 124 to 201 and 218 to 294) (34,37,62) (Fig. 1A). The amphipathic ␣ helix appears to be important for interaction with TBP (34, 37) and several transcriptional activators such as the herpes simplex virus VP16 protein (62).Members of the steroid/thyroid hormone receptor gene family are sequence-specific DNA-binding proteins that play important roles in gene regulation. The steroid hormone receptor subfamily includes the receptors which mediate the effects of glucocorticoids, progestins, mineralocorticoids, androgens, and estrogens (12, 16). The thyroid/retinoid receptor subfamily (16, 21) includes receptors that mediate the effects of thyroid hormone (3,5,3Ј-triiodo-L-thyronine [T3]), all-trans retinoic acid, 9-cis retinoic acid, and 1,25-dihydroxyvitamin D 3 as well as several orphan receptors (e.g., COUP-TF and c-ErbA␣2) whose ligands, if any, are unknown (26,27,44). Steroid/thyroid receptors bind to specific DNA sequences known as hormone response elements (HREs) and mediate ligand-dependent ac-

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“…Furthermore, nuclear receptors for steroid and thyroid hormones form dimers with other receptors through an unknown mechanism. For example, the thyroid hormone receptor (TR) (3,4), binding to different repeats of the AGGTCA motif, can form homodimers or heterodimers with other proteins, such as TR auxiliary protein (TRAP) (5), the retinoic acid receptor (RAR) (6,7), or the retinoid X receptor (RXR) (8)(9)(10)(11).…”

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confidence: 99%

Identification and analysis of all components of a gel retardation assay by combination with immunoblotting.

Demczuk

Harbers

Vennström

1993

Proc. Natl. Acad. Sci. U.S.A.

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A better method was developed for analysis and identification of protein and DNA components of gel-shift assays. The protein-DNA complexes, separated in polyacrylamide gels, were transferred onto stacked nitroceDulose and anion-exchange membranes. The proteins, bound to nitrocellulose, were identified by immunoblotting, while the DNA, which bound only to the anion-exchange membrane, was detected by autoradiography. The technique readily identified thyroid hormone receptors interacting with response elements representing inverted or direct repeats of the consensus halfsite AGGTCA. In addition, specific antisera identified both the thyroid hormone and the retinoic acid receptors in het-

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Binding characteristics of the thyroid hormone receptor homo- and heterodimers to consensus AGGTCA repeat motifs.

Cited by 46 publications

References 31 publications

DNA Recognition by Normal and Oncogenic Thyroid Hormone Receptors

DNA Recognition by Normal and Oncogenic Thyroid Hormone Receptors

A 10-Amino-Acid Sequence in the N-Terminal A/B Domain of Thyroid Hormone Receptor α Is Essential for Transcriptional Activation and Interaction with the General Transcription Factor TFIIB

Identification and analysis of all components of a gel retardation assay by combination with immunoblotting.

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