The thyroid hormone receptor antagonizes CREB-mediated transcription

Méndez-Pertuz, Marinela; Sánchez-Pacheco, Aurora; Aranda, Ana

doi:10.1093/emboj/cdg295

Cited by 66 publications

(66 citation statements)

References 61 publications

(82 reference statements)

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“…In agreement with this, we now show that ATF-2 transcriptional activity is markedly enhanced upon expression of Ha-ras val12 and is repressed by T3 in hepatocarcinoma cells. TRs can antagonize CREmediated transcription without binding to this motif by a direct interaction of the receptor with the b-Zip factor CREB (Mendez-Pertuz et al, 2003) and we now observe that the receptors can also interact with ATF-2. Whereas the liganded TRb1 represses cyclin D1 expression, it has been reported that repression via the CRE is lost in the TRb1 mutant PV (Furumoto et al, 2005).…”

Section: Discussionsupporting

confidence: 56%

“…In agreement with this, mutation of CRE or Sp1 sites in the cyclin D1 promoter reduced induction by Ha-ras val12 and combined mutation of both motifs essentially abolished its effect (Figure 4a). TRs can interact with CREB inhibiting its phosphorylation (Mendez-Pertuz et al, 2003), and, as shown in Figure 4b, TRb1 also interacts directly with the b-Zip factor ATF-2 (activation transcription factor-2) in pulldown assays. In addition, cotransfection of a dominantnegative ATF-2 blocked the promoter response to Ha-ras val12 (Figure 4c), showing the implication of CRE-binding factors.…”

Section: Antagonism Of Ras Responses By Trb1mentioning

confidence: 95%

“…Thus, some nuclear receptors can transrepress the activity of target gene promoters that carry AP-1, CRE (cAMP-response element) or NF-kB sites (Pfahl, 1993;Mendez-Pertuz et al, 2003;Pascual and Glass, 2006;De Bosscher et al, 2008). The receptors do not bind to these elements 'in vitro', but 'in vivo' the liganded receptors can be tethered to the promoter through protein-protein interactions (Rogatsky et al, 2001;Mendez-Pertuz et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Thyroid hormone receptor β1 domains responsible for the antagonism with the ras oncogene: role of corepressors

et al. 2010

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The thyroid hormone receptor (TR) is a suppressor of rasmediated responses. To characterize the receptor domains involved in this function, we analyzed a panel of TRb1 mutants for their ability to interfere with ras-driven cyclin D1 activation, formation of transformation foci and tumor growth in nude mice. Our results show that the domains and mechanisms responsible for the anti-transforming and anti-tumorigenic actions of the receptor are divergent from those operating in classical T3-dependent transcriptional activation. TRb1 mutants that do not bind coactivators and do not transactivate retained the capacity of suppressing cellular transformation and tumor growth, whereas selective mutations in the hinge region affecting corepressors recruitment abolished these actions, while preserving ligand-dependent transcription. There was a strict parallelism between anti-transforming activity of the various mutants and their ability to antagonize cyclin D1 stimulation by ras, indicating that transrepression mechanisms may have an important function in suppression of the transforming effects of the oncogene by TRb1. The inhibitory action of T3 on transformation was further enhanced after over-expression of corepressors, while corepressor depletion by means of small-interference RNA reversed significantly hormonal action. This shows an important functional role of endogenous corepressors in suppression of ras-mediated transformation and tumorigenesis by TRb1

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Section: Discussionsupporting

confidence: 56%

Section: Antagonism Of Ras Responses By Trb1mentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Thyroid hormone receptor β1 domains responsible for the antagonism with the ras oncogene: role of corepressors

et al. 2010

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“…TR has been shown to bind other transcription factors and cofactors via its DBD (Poirier et al 2005, Matsushita et al 2007). An interesting interaction is the reported interaction of TR with cAMP response element binding protein (CREB), which is ensured via the DBD of TR (Mendez-Pertuz et al 2003, Furumoto et al 2005. Protein-protein interaction leads to an antagonism of CREB-mediated transcription by TR and vice versa.…”

Section: Discussionmentioning

confidence: 99%

The role of thyroid hormone receptor DNA binding in negative thyroid hormone-mediated gene transcription

Wulf¹,

Wetzel²,

Kebenko³

et al. 2008

Journal of Molecular Endocrinology

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Thyroid hormone 3,3 0 ,5-tri-iodothyronine (T 3 ) regulates gene expression in a positive and negative manner. Here, we analyzed the regulation of a positively (mitochondrial glycerol-3-phosphate dehydrogenase) and negatively T 3 -regulated target gene (TSHa). Thyroid hormone receptor (TR) activates mGPDH but not TSH promoter fragments in a mammalian one-hybrid assay. Furthermore, we investigated functional consequences of targeting TR to DNA independent of its own DNA-binding domain (DBD). Using a chimeric fusion protein of the DBD of yeast transcription factor Gal4 with TR, we demonstrated a positive regulation of gene transcription in response to T 3 . T 3 -mediated activation of this chimeric protein is further increased after an introduction of point mutations within the DBD of TR. Moreover, we investigated the capacity of TR to negatively regulate gene transcription on a DNA-tethered cofactor platform. A direct binding of TR to DNA via its own DBD is dispensable in this assay. We investigated functional consequences of point mutations affecting different domains of TR. Our data indicate that the DBD of TR plays a key role in direct DNA binding on positively but not on negatively T 3 -regulated target genes. Nevertheless, the DBD is involved in mediating negative gene regulation independent of its capacity to bind DNA.

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“…TRs can also modulate expression of genes that do not contain a hormone response element by modulating the activity of other transcription factors and signaling pathways (2), including activator protein-1 (AP-1)-, cyclic AMP-response element-, and nuclear factor-B (NF-B)-dependent pathways (3)(4)(5)(6)(7).…”

mentioning

confidence: 99%

The Thyroid Hormone Receptors as Modulators of Skin Proliferation and Inflammation

Contreras‐Jurado

García-Serrano

Gómez-Ferrerı́a

et al. 2011

Journal of Biological Chemistry

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The actions of thyroid hormones are mediated by binding to nuclear receptors, TR␣ 4 and TR␤, that act as ligand-dependent transcription factors by association, generally as heterodimers with retinoid X receptors, with thyroid hormone response elements located in regulatory regions of target genes (1). TRs can also modulate expression of genes that do not contain a hormone response element by modulating the activity of other transcription factors and signaling pathways (2), including activator protein-1 (AP-1)-, cyclic AMP-response element-, and nuclear factor-B (NF-B)-dependent pathways (3-7).Studies with knock-out (KO) mice for TRs obtained by homologous recombination have indicated that KO mice for ␣1 and ␤ TR isoforms have different phenotypes (8 -10) and that the double KO mice, surprisingly, survive (11), indicating that these receptors are not required for viability. Although these animals show extreme resistance to thyroid hormones, they exhibit a milder phenotype than hypothyroid mice, indicating divergent consequences for hormone versus receptor deficiency for some actions.Although the skin is a target tissue for thyroid hormone action, no studies on the skin phenotype in TR KO mice have been reported. TR␣ and TR␤ mRNAs are present in the skin (12-15), and these receptors can regulate either positively or negatively the expression of selected keratins in cultured cells (16 -19). Clinical evidence (19 -27) as well as studies in hypothyroid mice and rats (28 -30) also suggest that thyroid hormones could be involved in epidermal proliferation and differentiation, hair growth, and wound healing besides affecting the function of dermal fibroblasts. A question emerging from these studies is how to distinguish between effects due to altered thyroid hormone levels and effects due to expression of specific TR isoforms.The TR KO mice represent an excellent model for the analysis of the role of these receptors in the skin and its response to hyperproliferative stimuli. Topical application of 12-O-tetradecanolyphorbol-13-acetate (TPA) to mouse skin is a well known model for induction of skin hyperproliferation and also promotes a strong inflammatory reaction that activates multiple immunostimulatory pathways. The skin response to TPA is associated with activation of several intracellular pathways (e.g. mitogen-activated protein kinases (MAPKs), AKT, NF-B, STAT3, and AP-1) as well as an increase in the content of chemical mediators, such as cytokines, chemokines, vasoactive peptides, prostaglandins, leukotrienes, and nitric oxide among others (31)(32)(33)(34).In this work, we have investigated skin proliferation and inflammation, before and after TPA application, in mice lacking TR␣1, TR␤, or both genes, comparing these responses with those of hypothyroid animals to distinguish the specific contributions of receptor expression and activation. We found that TRs and thyroid hormones are required for skin homeostasis after TPA treatment and that both receptor genes contribute to

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The thyroid hormone receptor antagonizes CREB-mediated transcription

Cited by 66 publications

References 61 publications

Thyroid hormone receptor β1 domains responsible for the antagonism with the ras oncogene: role of corepressors

Thyroid hormone receptor β1 domains responsible for the antagonism with the ras oncogene: role of corepressors

The role of thyroid hormone receptor DNA binding in negative thyroid hormone-mediated gene transcription

The Thyroid Hormone Receptors as Modulators of Skin Proliferation and Inflammation

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