Some new twists in the regulation of gene expression by thyroid hormone and retinoic acid receptors

Glass, Chris K.

doi:10.1677/joe.0.1500349

Cited by 69 publications

(54 citation statements)

References 37 publications

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“…Wild-type TRs operate as hormone-regulated transcription factors that bind to specific DNA sequences (denoted thyroid response elements, or TREs) and regulate transcription of adjacent target genes (Mangelsdorf et al, 1995;Glass, 1996;Apriletti et al, 1998;Ribeiro et al, 1998;Beato and Klug, 2000;Zhang and Lazar, 2000). TRs bind to TREs, recruit corepressors (such as NCoR and SMRT), and typically repress transcription in the absence of hormone; conversely, the binding of T3 hormone induces a conformational change in TRs that results in corepressor release, the recruitment of coactivators (such as SRC-1), and transcriptional activation (Glass, 1996;Horwitz et al, 1996;Koenig, 1998;Ordentlich et al, 2001;Lee and Kang, 2002;. TRs can also regulate target genes indirectly through protein-protein contacts with other transcription factors.…”

Section: Introductionmentioning

confidence: 99%

Thyroid hormone receptors mutated in liver cancer function as distorted antimorphs

Chan

Privalsky

2006

Oncogene

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Aberrant thyroid hormone receptors (TRs) are found in over 70% of the human hepatocellular carcinomas (HCCs) analysed. To better understand the role(s) of these TR mutants in this neoplasia, we analysed a panel of HCC mutant receptors for their molecular properties. Virtually all HCC-associated TR mutants tested retained the ability to repress target genes in the absence of T3, yet were impaired in T3-driven gene activation and functioned as dominant-negative inhibitors of wild-type TR activity. Intriguingly, the HCC TRa1 mutants exerted dominantnegative interference at all T3 concentrations tested, whereas the HCC TRb1 mutants were dominant-negatives only at low and intermediate T3 concentrations, reverting to transcriptional activators at higher hormone levels. The relative affinity for the SMRT versus N-CoR corepressors was detectably altered for several of the HCC mutant TRs, suggesting changes in corepressor preference and recruitment compared to wild type. Several of the TRa HCC mutations also altered the DNA recognition properties of the encoded receptors, indicating that these HCC TR mutants may regulate a distinct set of target genes from those regulated by wild-type TRs. Finally, whereas wild-type TRs interfere with c-Jun/AP-1 function in a T3-dependent fashion and suppress anchorageindependent growth when ectopically expressed in HepG2 cells, at least certain of the HCC mutants did not exert these inhibitory properties. These alterations in transcriptional regulation and DNA recognition appear likely to contribute to oncogenesis by reprogramming the differentiation and proliferative properties of the hepatocytes in which the mutant TRs are expressed.

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Section: Introductionmentioning

confidence: 99%

Thyroid hormone receptors mutated in liver cancer function as distorted antimorphs

Chan

Privalsky

2006

Oncogene

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“…Consensus RAREs have been described which consist of direct repeats (DR) of the sequence PuG(G/T)TCA with two or five nucleotides intervening the repeats (a DR2 or a DR5 element, respectively). RAREs are, however, highly polymorphic, and a number of variant motifs have been described (Huang et al, 2002;Glass, 1996). Retinoid signaling is also tightly controlled by the opposing actions of RALDH2, which is essential for the generation of most embryonic RA, and CYP26 members, which catabolizes RA (Swindell et al, 1999;Sakai et al, 2001;Abu-Abed et al, 1998;MacLean et al, 2001;Perlmann, 2002).…”

Section: Introductionmentioning

confidence: 99%

Retinoic acid regulates a subset of Cdx1 function in vivo

2003

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mechanism or through an intermediary; these mechanisms are not necessarily exclusive. In this regard, we have found that Cdx1 may serve as such an intermediary. Cdx1 encodes a homeobox transcription factor that is crucial for normal somitic expression of several Hox genes, and is regulated by retinoid signalling in vivo and in vitro likely through an atypical RARE in the proximal promoter. In order to more fully understand the relationship between retinoid signalling, Cdx1 expression and AP patterning, we have derived mice in which the RARE has been functionally inactivated. These RARE-null mutants exhibit reduced expression of Cdx1 at all stages examined, vertebral homeotic transformations and altered Hox gene expression which correlates with certain of the defects seen in Cdx1-null offspring. These findings are consistent with a pivotal role for retinoid signalling in governing a subset of expression of Cdx1 crucial for normal vertebral patterning. Research article 6556 retinoic acid (RA) plays a crucial role (Marshall et al., 1996). RA can induce Hox genes in embryocarcinoma cells in a manner reminiscent of the normal temporal activation of Hox expression, with 3′ genes from a given cluster responding earlier, and to lower concentrations of RA, than more 5′ members (Boncinelli et al., 1991;Simeone et al., 1990). In vivo, administration of exogenous RA to mouse embryos between E7.5 and E8.5 typically results in anteriorization of a number of Hox genes in a manner that correlates with posterior vertebral homeotic transformations (Conlon and Rossant, 1992;Kessel, 1992;Kessel and Gruss, 1991). Similar effects are also elicited by RA on expression of Hox genes in the CNS and concomitant perturbation of rhombomere patterning (Gavalas and Krumlauf, 2000;Gould et al., 1998;Marshall et al., 1992).The RA signal is transduced by the RA receptors (RARα, RARβ, RARγ and their isoforms). RARs belong to the family of ligand-inducible nuclear receptors and regulate expression of retinoid target genes as heterodimers with a retinoid X receptor (RXRα, RXRβ, RXRγ) partner. RXR-RAR heterodimers function by binding to cis-acting regulatory sequences (RAREs) present in the promoter region of target genes (Chambon, 1996;Mangelsdorf et al., 1995). Consensus RAREs have been described which consist of direct repeats (DR) of the sequence PuG(G/T)TCA with two or five nucleotides intervening the repeats (a DR2 or a DR5 element, respectively). RAREs are, however, highly polymorphic, and a number of variant motifs have been described (Huang et al., 2002;Glass, 1996). Retinoid signaling is also tightly controlled by the opposing actions of RALDH2, which is essential for the generation of most embryonic RA, and CYP26 members, which catabolizes RA (Swindell et al., 1999;Sakai et al., 2001; Abu-Abed et al., 1998;MacLean et al., 2001;Perlmann, 2002).A role for endogenous retinoid signaling in affecting Hox expression and AP patterning is supported by numerous studies (Gavalas et al., 1998;Huang et al., 1998;Zhang et al., 1997). Vertebral homeos...

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“…Nuclear receptors operate by binding to specific promoter elements on DNA and by modulating transcription of adjacent target genes in response to hormone ligand (3,(7)(8)(9). The nuclear receptors include, among others, the thyroid hormone receptors (TRs), 1 the retinoic acid receptors (RARs), and the retinoid X receptors (RXRs) (3-5, 7, 10, 11).…”

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confidence: 99%

Alternative mRNA Splicing of SMRT Creates Functional Diversity by Generating Corepressor Isoforms with Different Affinities for Different Nuclear Receptors

Goodson¹,

Jonas

Privalsky

2005

Journal of Biological Chemistry

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Many eukaryotic transcription factors are bimodal in their regulatory properties and can both repress and activate expression of their target genes. These divergent transcriptional properties are conferred through recruitment of auxiliary proteins, denoted coactivators and corepressors. Repression plays a particularly critical role in the functions of the nuclear receptors, a large family of ligand-regulated transcription factors involved in metazoan development, differentiation, reproduction, and homeostasis. The SMRT corepressor interacts directly with nuclear receptors and serves, in turn, as a platform for the assembly of a larger corepressor complex. We report here that SMRT is expressed in cells by alternative mRNA splicing to yield two distinct variants or isoforms. We designate these isoforms SMRT␣ and SMRT and demonstrate that these isoforms have significantly different affinities for different nuclear receptors. These isoforms are evolutionarily conserved and are expressed in a tissue-specific manner. Our results suggest that differential mRNA splicing serves to customize corepressor function in different cells, allowing the transcriptional properties of nuclear receptors to be adapted to different contexts.Nuclear receptors are transcription factors that play multiple roles in metazoan development and physiology (1-6). Nuclear receptors operate by binding to specific promoter elements on DNA and by modulating transcription of adjacent target genes in response to hormone ligand (3, 7-9). The nuclear receptors include, among others, the thyroid hormone receptors (TRs), 1 the retinoic acid receptors (RARs), and the retinoid X receptors (RXRs) (3-5, 7, 10, 11). Each of these receptors localizes to the nucleus and binds to DNA in both the absence and presence of hormone ligand. These receptors can repress transcription of their target genes in the absence of hormone, but activate target gene transcription upon binding to hormone agonist (3, 7-9, 12, 13). This bimodal transcriptional regulation is accomplished through a hormone-regulated exchange of a corepressor complex, found on the nuclear receptor in the absence of hormone, for a coactivator complex recruited in the presence of hormone agonist (14). Corepressor and coactivator protein complexes regulate transcription through direct interaction with the basal transcription machinery and through modification of chromatin structure (15).Both activation and repression are essential for correct receptor function. For example, RAR-mediated repression is required for appropriate anterior/posterior segregation in vertebrates, and disruption leads to aberrant head formation during murine development (16). TR-mediated repression is required for correct Xenopus larval development, and abrogation of repression leads to premature metamorphosis (17). Aberrations in the regulation of repression can result in human disease. For example, resistance to thyroid hormone syndrome, an inherited endocrine disorder, has been mapped to mutations in TRs that disrupt the hormone-...

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Some new twists in the regulation of gene expression by thyroid hormone and retinoic acid receptors

Cited by 69 publications

References 37 publications

Thyroid hormone receptors mutated in liver cancer function as distorted antimorphs

Thyroid hormone receptors mutated in liver cancer function as distorted antimorphs

Retinoic acid regulates a subset of Cdx1 function in vivo

Alternative mRNA Splicing of SMRT Creates Functional Diversity by Generating Corepressor Isoforms with Different Affinities for Different Nuclear Receptors

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