Differential ligand-dependent interactions between the AF-2 activating domain of nuclear receptors and the putative transcriptional intermediary factors mSUG1 and TIF1.

Baur, Elmar vom; Zechel, Christina; Heery, David M.; Heine, Matthias J.S.; Garnier, Jean‐Marie; Vivat, Valérie; Douarin, Bertrand Le; Gronemeyer, Hinrich; Chambon, Pierre; Losson, Régine

doi:10.1002/j.1460-2075.1996.tb00339.x

Cited by 372 publications

(269 citation statements)

References 75 publications

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“…This selectivity is consistent with previous studies on putative mammalian mediators, which revealed their differential interaction with the AF-2 ADs of various NRs in spite of the similarity of their respective AF-2 AD core motif (vom Baur et al 1996;Thé not et al 1997). Thus, the activity of the RAR␣ AF-2 constructs that can activate transcription in a RA-dependent manner in yeast (Heery et al 1993) is probably not mediated by Ada3.…”

Section: Ada3 a Coactivator/mediator For The Ligand-dependent Activasupporting

confidence: 92%

The yeast Ada complex mediates the ligand-dependent activation function AF-2 of retinoid X and estrogen receptors

Baur¹,

Harbers²,

Um³

et al. 1998

Genes & Development

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Nuclear receptors (NRs) represent a large family of ligand-inducible transcriptional regulators that control complex developmental and homeostatic events in vertebrates by binding as homodimers or heterodimers to cognate DNA response elements present in target genes. NRs display a modular structure, with five to six distinct regions (denoted A-E/F; see Fig. 1A). The amino-terminal A/B region contains an autonomous activation function (AF-1), the highly conserved region C belongs to the DNA-binding domain (DBD), and the carboxy-terminal E region contains the ligand-binding domain (LBD), a dimerization surface and a ligand-dependent transcriptional activation function, AF-2 (for reviews and refs, see Mangelsdorf et al. 1995;Chambon 1996;Perlman and Evans 1997). The core of the AF-2 activating domain (AF-2 AD core; see Fig. 1A) has been characterized in the carboxy-terminal part of the E region and corresponds to the conserved amphipathic ␣ helix 12 of the LBD. Upon ligand binding, this helix is thought to fold back over the LBD to generate interacting surface(s) for the binding of transcriptional intermediary factors (TIFs, also denoted coactivators or mediators), whose effects ultimately result in the remodeling of the structure of the chromatin template and/or in the stimulation of initiation of RNA synthesis by the general transcription machinery (for reviews and references, see Chambon 1996;Wurtz et al. 1996;Glass et al. 1997).Although the yeast Saccharomyces cerevisiae does not possess endogenous NRs, it has been shown that a number of NRs, including the estrogen receptor (ER, now designated ER␣), the glucocorticoid receptor (GR), the retinoic acid (RA) receptors (RARs and RXRs), and the thyroid hormone receptor (TRs) can function as liganddependent transactivators in yeast (Metzger et al. , 1992Schena and Yamamoto 1988;Hall et al. 1993;Heery et al. 1993; and references therein). As in vertebrates (Chambon 1996 and references therein), the AF-1 and AF-2 of ER␣, RAR␣, and RXR␣ can activate transcription independently and synergistically in yeast White et al. 1988;Pierrat et al. 1992; Heery et al.1993; and our unpublished results

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Section: Ada3 a Coactivator/mediator For The Ligand-dependent Activasupporting

confidence: 92%

The yeast Ada complex mediates the ligand-dependent activation function AF-2 of retinoid X and estrogen receptors

Baur¹,

Harbers²,

Um³

et al. 1998

Genes & Development

Self Cite

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“…Surprisingly, we found that Hr interacts with TR. Previously identified proteins that interact with TR have been shown to interact with multiple nuclear receptors (9,10,(14)(15)(16)(17)(18)(19)(20)(21). In contrast, of the retinoid and steroid receptors tested here, Hr interacts only with TR.…”

mentioning

confidence: 79%

The product of a thyroid hormone-responsive gene interacts with thyroid hormone receptors

Thompson

Bottcher

1997

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

129

106

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Thyroid hormone is a critical mediator of central nervous system (CNS) development, acting through nuclear receptors to modulate the expression of specific genes. Transcription of the rat hairless (hr) gene is highly upregulated by thyroid hormone in the developing CNS; we show here that hr is directly induced by thyroid hormone. By identifying proteins that interact with the hr gene product (Hr), we find that Hr interacts directly and specifically with thyroid hormone receptor (TR)-the same protein that regulates its expression. Unlike previously described receptorinteracting factors, Hr associates with TR and not with retinoic acid receptors (RAR, RXR). Hr can act as a transcriptional repressor, suggesting that its interaction with TR is part of a novel autoregulatory mechanism.Many factors, both genetic and environmental, contribute to the formation and function of the mammalian central nervous system (CNS). An essential component of these processes is thyroid hormone (TH); if thyroid hormone levels are perturbed, abnormal development ensues, resulting in neurological deficits that include severe mental retardation (1-4). The effects of TH are mediated through the action of specific nuclear receptor proteins (5, 6). Thyroid hormone receptors (TR) act by binding to specific DNA sequences and subsequently activating or repressing the transcription of nearby genes in response to hormone binding (7,8). Several proteins that interact with TR and other nuclear hormone receptors, including both coactivators and corepressors, have been identified (9, 10).Although much is known about the mechanism of action of TR and other nuclear receptors, far less is known about the genes regulated by these receptors. We have shown that the rat hairless (hr) gene is highly up-regulated (Ͼ10-fold) by thyroid hormone in developing brain (11). The rapid induction (Ͻ4 hr) occurs even in the absence of protein synthesis, suggesting that hr is directly regulated by TR. Direct target genes are particularly important because such genes likely constitute the first step in the genetic program responsible for TH-mediated aspects of neural development. We show here that the upstream regulatory region of the hr gene includes a potent thyroid hormone response element (TRE), indicating that hr is indeed a direct target of TR.The murine hr locus was originally identified as a spontaneous mutation caused by an endogenous retrovirus (12). The hr gene is expressed predominantly in skin and brain; the mutant phenotype in skin is progressive hair loss and increased susceptibility to cancer, while the neurological phenotype has not yet been described (11, 13). The hr gene encodes a putative protein of approximately 127 kDa that lacks homology to known structural motifs other than a cluster of cysteine residues proposed to form a zinc finger (13). Toward defining the function of the hr gene product (Hr), we identified proteins that interact with Hr. Surprisingly, we found that Hr interacts with TR. Previously identified proteins that interact wit...

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“…Target gene activation is not required for catabolism (Zhu et al, 1999). The activated AF-2 domain was previously shown to bind the SUG-1 component of the proteasome 19 S complex vom Baur et al, 1996), providing a direct link between AF-2 activation and the proteasome-dependent degradation ( Figure 1). Not surprisingly, given the universal use of the AF-2 domain in nuclear receptors, such ligand-induced nuclear receptor catabolism has been described for a number of them (ERa, PPARg, PR.…”

Section: The Playersmentioning

confidence: 93%

“…We had proposed that RA-induced, AF-2 dependent, degradation of the normal RARa could derepress targets independently of an AF-2-dependent transcriptional activation (Zhu et al, 1999). Taken that the molecular determinants in the receptor required for coactivator binding and degradation are very similar, if not identical (vom Baur et al, 1996;Zhu et al, 1999), it may not be so easy to discriminate between the activation and the derepression models. Assuming that derepression through degradation is indeed critical for di erentiation induction, arsenic, which selectively degrades PML/RARa, could act through the same process.…”

Section: What Are the Functional Consequences Of Pml/rara Degradationmentioning

confidence: 99%

Pathways of retinoic acid- or arsenic trioxide-induced PML/RARα catabolism, role of oncogene degradation in disease remission

Zhu

Lallemand-Breitenbach

2001

Oncogene

148

130

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Although there is evidence to suggest that PML/RARa expression is not the sole genetic event required for the development of acute promyelocytic leukemia (APL), there is little doubt that the fusion protein plays a central role in the initiation of leukemogenesis. The two therapeutic agents, retinoic acid and arsenic, that induce clinical remissions in APL, both target the oncogenic fusion protein, representing the ®rst example of oncogene-directed cancer therapy. This review focuses on the molecular mechanisms accounting for PML/RARa degradation. Each drug targets a speci®c moiety of the fusion protein (RARa for retinoic acid, PML for arsenic) to the proteasome. Moreover, both activate a common caspase-dependent cleavage in the PML part of the fusion protein. Speci®c molecular determinants (the AF2 transactivator domain of RARa for retinoic acid and the K160 SUMO-binding site in PML for arsenic) are respectively implicated in RA-or arsenic-triggered catabolism. The respective roles of PML/RARa activation versus its catabolism are discussed with respect to di erentiation or apoptosis induction in the context of single or dual therapies. Oncogene (2001) 20, 7257 ± 7265.

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Differential ligand-dependent interactions between the AF-2 activating domain of nuclear receptors and the putative transcriptional intermediary factors mSUG1 and TIF1.

Cited by 372 publications

References 75 publications

The yeast Ada complex mediates the ligand-dependent activation function AF-2 of retinoid X and estrogen receptors

The yeast Ada complex mediates the ligand-dependent activation function AF-2 of retinoid X and estrogen receptors

The product of a thyroid hormone-responsive gene interacts with thyroid hormone receptors

Pathways of retinoic acid- or arsenic trioxide-induced PML/RARα catabolism, role of oncogene degradation in disease remission

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