Identification of TRACs (T3 receptor-associating cofactors), a family of cofactors that associate with, and modulate the activity of, nuclear hormone receptors.

Sande, Stephen; Privalsky, Martin L.

doi:10.1210/mend.10.7.8813722

Cited by 95 publications

(84 citation statements)

References 29 publications

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“…In vertebrates, corepressors are encoded by two known, interrelated loci, denoted SMRT (or TRAC) and N-CoR (or RIP13), with each locus expressed as a variety of alternatively spliced mRNAs (e.g., TRAC-1, TRAC-2, RIP13A;. Mutant T3Rs exhibiting aberrant interactions with corepressors display aberrant transcriptional regulatory properties (26)(27)(28)(29)33). Therefore we asked if the PML-RAR␣ and PLZF-RAR␣ chimeras exhibited similar aberrant interactions with corepressors that might contribute to their oncogenic proclivities.…”

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confidence: 99%

“…In the absence of hormone, RARs (and the closely related thyroid hormone receptors, T3Rs) act as transcriptional repressors, a process mediated, in part, by the physical association of these receptors with ancillary proteins termed corepressors (26)(27)(28)(29)(30)(31)(32)(33). Addition of hormone converts these receptors into transcriptional activators, a process that correlates with dissociation of the corepressors from the receptor and a corresponding recruitment of a novel set of coactivator proteins (26)(27)(28)(29)(30)(31)(32)(33)(34).…”

mentioning

confidence: 99%

“…Addition of hormone converts these receptors into transcriptional activators, a process that correlates with dissociation of the corepressors from the receptor and a corresponding recruitment of a novel set of coactivator proteins (26)(27)(28)(29)(30)(31)(32)(33)(34). In vertebrates, corepressors are encoded by two known, interrelated loci, denoted SMRT (or TRAC) and N-CoR (or RIP13), with each locus expressed as a variety of alternatively spliced mRNAs (e.g., TRAC-1, TRAC-2, RIP13A; refs.…”

mentioning

confidence: 99%

“…In vertebrates, corepressors are encoded by two known, interrelated loci, denoted SMRT (or TRAC) and N-CoR (or RIP13), with each locus expressed as a variety of alternatively spliced mRNAs (e.g., TRAC-1, TRAC-2, RIP13A; refs. [26][27][28][29][30][31][32][33]. Mutant T3Rs exhibiting aberrant interactions with corepressors display aberrant transcriptional regulatory properties (26)(27)(28)(29)33).…”

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confidence: 99%

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SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor α (RARα) and PLZF-RARα oncoproteins associated with acute promyelocytic leukemia

Hong

Gourichon

Wong

et al. 1997

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

329

277

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Retinoic acid receptors (RARs) are hormone-regulated transcription factors that control key aspects of normal differentiation. Aberrant RAR activity may be a causal factor in neoplasia. Human acute promyelocytic leukemia, for example, is tightly linked to chromosomal translocations that fuse novel amino acid sequences (denoted PML, PLZF, and NPM) to the DNA-binding and hormone-binding domains of RAR␣. The resulting chimeric receptors have unique transcriptional properties that may contribute to leukemogenesis. Normal RARs repress gene transcription by associating with ancillary factors denoted corepressors (also referred to as SMRT, N-CoR, TRAC, or RIP13). We report here that the PML-RAR␣ and PLZF-RAR␣ oncoproteins retain the ability of RAR␣ to associate with corepressors, and that this corepressor association correlates with certain aspects of the leukemic phenotype. Unexpectedly, the PLZF moiety itself can interact with SMRT corepressor. This interaction with corepressor is mediated, in part, by a POZ motif within PLZF. Given the presence of POZ motifs in a number of known transcriptional repressors, similar interactions with SMRT may play a role in transcriptional silencing by a variety of both receptor and nonreceptor transcription factors.Retinoids regulate many aspects of vertebrate cell proliferation and differentiation through receptors that function as hormone-regulated transcription factors (1-6). Two major classes of retinoid receptors have been identified: retinoic acid receptors (RARs) and retinoid X receptors (RXRs) (3-6). Both RARs and RXRs bind to specific sites on the DNA, and they can activate or repress expression of adjacent target genes (1-6). Aberrant RARs appear to play a crucial role in human acute promyelocytic leukemia (APL) (7-15). In over 95% of all APL patients, specific chromosomal translocations create abnormal RARs by replacing the N terminus of RAR␣ with novel ORFs. The breakpoint in RAR␣ is identical in all cases, whereas the nature of the novel N-terminal sequences can vary. In the common t(15;17) translocation, the RAR␣ N terminus is replaced with an ORF denoted PML (for promyelocytic leukemia) (7-12). Alternatively, t(11;17) and t(5;17) translocations result in chimeric proteins denoted PLZF (promyelocytic leukemia zinc finger)-RAR␣ and NPM (nucleophosmin)-RAR␣, respectively (13-15). Although possessing a number of recognizable structural motifs, including several prevalent in transcription factors, the PML, PLZF, and NPMderived sequences exhibit little structural interrelatedness, and the functions of these proteins in the normal cell are not fully understood (reviewed in refs. 16-18).The near-invariant association of acute promyelocytic leukemia with the expression of chimeric RAR␣ proteins, and the ability of retinoids to drive leukemias bearing the PML-RAR␣ translocation into differentiation and clinical remission (16-18), suggest an active role for these chimeras in conferring the leukemogenic phenotype. Furthermore, ectopic expression of PML-RAR␣ in murine or av...

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mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

“…In vertebrates, corepressors are encoded by two known, interrelated loci, denoted SMRT (or TRAC) and N-CoR (or RIP13), with each locus expressed as a variety of alternatively spliced mRNAs (e.g., TRAC-1, TRAC-2, RIP13A; refs. [26][27][28][29][30][31][32][33]. Mutant T3Rs exhibiting aberrant interactions with corepressors display aberrant transcriptional regulatory properties (26)(27)(28)(29)33).…”

mentioning

confidence: 99%

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SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor α (RARα) and PLZF-RARα oncoproteins associated with acute promyelocytic leukemia

Hong

Gourichon

Wong

et al. 1997

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

329

277

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“…As a control for specific expression of transfected h-TR␤1, lane 2 shows that when an identical expression plasmid lacking the coding sequence of h-TR␤1 was used, no expression of h-TR␤1 was detected. Transfection of this TR␤1-less vector had no effect on the induction of TR␤1 in COS-1 cells by OA, as the intensity of the TR␤1 band seen was identical to that in its absence (lane 8 versus lane 7). The intensity of the TR␤1 band in the presence of OA (lane 9) was slightly higher than that in the absence of OA (lane 3), reflecting the combined intensities of the endogenous and the transfected TR␤1.…”

Section: Cell Type-and Tr Isoform-dependent Induction Of Expression Omentioning

confidence: 89%

Tissue-specific Stabilization of the Thyroid Hormone β1 Nuclear Receptor by Phosphorylation

Ting

Bhat

Wong

et al. 1997

Journal of Biological Chemistry

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The present study evaluated the expression and regulation of endogenous thyroid hormone receptors (TRs) in cultured cells. In COS-1 cells, the endogenous TR, subtype ␤1 (TR␤1), but not subtype ␤2 or ␣1, was induced to express by okadaic acid (OA) in a concentrationdependent manner. The induced TR␤1 had immunoreactivity and partial V8 proteolytic maps similar to those of the transfected and in vitro translated human TR␤1 (h-TR␤1). The OA-induced expression of endogenous TR␤1 was, however, not observed in a variety of other cultured cell lines tested, indicating that the induction was cell type-dependent. TR␤1 induced by OA was a multisite phosphorylated protein, in which serine and threonine in a ratio of 10:1 were phosphorylated. The induced TR␤1 was functional as it could mediate the thyroid hormone-dependent transcriptional activity via several thyroid hormone response elements. The induction of endogenous TR␤1 expression by OA was not accompanied by an increase in mRNA levels but was the result of an increase in the stability of the TR␤1 protein. This is the first report to indicate that one of the mechanisms by which the TR isoforms are differentially expressed is via the tissue-specific stabilization of the TR isoform proteins. Furthermore, this selective stability of TR␤1 could be conferred by phosphorylation.Thyroid hormone nuclear receptors (TRs) 1 are members of the steroid hormone/retinoic acid receptor superfamily. Two TR genes, TR␣ and TR␤, have been identified which are located on chromosome 17 and chromosome 3, respectively. Four isoforms, ␤1, ␤2, ␣1, and ␣2, are generated from each of two TR genes, ␣ and ␤, by alternative splicing (1, 2). They are transcription factors that regulate the expression of target genes by interacting with specific DNA sequences known as thyroid hormone response elements (TREs) in the promoter region of target genes (1, 2). The transcriptional activity of TRs is not only dependent on thyroid hormone 3,3Ј,5-triiodo-L-thyronine (T 3 ) but also on the type of TRE. Recent studies have indicated that the transcriptional activity of TRs is further modulated via interaction with four groups of cellular proteins: (a) members of the nuclear receptor superfamily, notably the retinoid X receptors (1, 2); (b) corepressors including p270/N-CoR (3), SMRT (4), TRUP (5), SHP (6), and TRACs (7); (c) coactivator SRC-1 (8); and (d) the tumor suppressor p53 (9). It is clear that regulation of the transcriptional activity of TRs is more complex than envisioned previously.One important but less well studied mode of modulation of TR activity is the regulation of TR expression at the protein level. TR␣1 and TR␤1 are differentially expressed at different developmental stages and at different levels in various tissues (10 -12). Moreover, using the specific T 3 binding activity and immunoreactivity as measures of the expressed receptor proteins, it was found that there are marked variations in the TR protein:mRNA ratios in different tissues (11, 12), suggesting isoform-and tissue-dependent posttra...

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Reduction of both RAR and RXR Levels Is Required to Maximally Alter Sensitivity of CA-OV3 Ovarian Tumor Cells to Growth Suppression by all-trans-Retinoic Acid☆

Zhu

Zhang

et al. 1997

Experimental Cell Research

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Identification of TRACs (T3 receptor-associating cofactors), a family of cofactors that associate with, and modulate the activity of, nuclear hormone receptors.

Cited by 95 publications

References 29 publications

SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor α (RARα) and PLZF-RARα oncoproteins associated with acute promyelocytic leukemia

SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor α (RARα) and PLZF-RARα oncoproteins associated with acute promyelocytic leukemia

Tissue-specific Stabilization of the Thyroid Hormone β1 Nuclear Receptor by Phosphorylation

Reduction of both RAR and RXR Levels Is Required to Maximally Alter Sensitivity of CA-OV3 Ovarian Tumor Cells to Growth Suppression by all-trans-Retinoic Acid☆

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