Retinoid-dependent in vitro transcription mediated by the RXR/RAR heterodimer.

Valcárcel, Rafael; Holz, Herbert; Jiménez, Carlota García-Hoz; Barettino, Domingo; Stunnenberg, Henk

doi:10.1101/gad.8.24.3068

Cited by 65 publications

(60 citation statements)

References 60 publications

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“…Comparison of structures of unliganded with liganded RA-receptors (Bourguet et al, 1995;Renaud et al, 1995;Wurtz et al, 1996) suggests that RA-binding induces a conformational change allowing the receptors to interact with several putative transcriptional intermediary factors required for RA-dependent transcriptional activity Schulman et al, 1995;Swaeld et al, 1995;vom Baur et al, 1995;May et al, 1996). Thus, through these positive cofactors/mediators, only the liganded-complex RA-receptors/myogenic factors might act eciently on the basal transcription machinery, as recently described for complexes involving nuclear receptors (Fondell et al, 1993;Lee et al, 1994;Valcarcel et al, 1994;Chakravarti et al, 1996). Consistent with this view, p300/CBP have been reported acting as coactivators for RA-receptors but also for the transcriptional factor MyoD (Chakravarti et al, 1996;Eckner et al, 1996;Yuan et al, 1996;Puri et al, 1997;Sartorelli et al, 1997).…”

Section: Molecular Mechanisms Of Myogenic Coactivation By Ra-receptorssupporting

confidence: 62%

Retinoic acid receptors and muscle b-HLH proteins: partners in retinoid-induced myogenesis

et al. 1998

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The results reported here indicate that retinoic acid (RA) induces growth arrest and dierentiation only in MyoDexpressing muscle cells. Transient transfection assays reveal a functional interaction between MyoD, a key myogenic regulator and RA-receptors, principal mediators of RA actions. Interestingly, we demonstrate that RXR-MyoD-containing complexes are recruited at speci®c MyoD DNA-binding sites in muscle cells.Furthermore, we also demonstrate that RA-receptors and the muscle basic helix ± loop ± helix (b-HLH) proteins interact physically. Mutational analysis suggests that this interaction occurs via the basic region of muscle b-HLH proteins and the DNA-binding domain of RAreceptors and is important for functional interactions between these two families of transcription factors. In conclusion, these results highlight novel interactions between two distinct groups of regulatory proteins that in¯uence cell growth and dierentiation.

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Section: Molecular Mechanisms Of Myogenic Coactivation By Ra-receptorssupporting

confidence: 62%

Retinoic acid receptors and muscle b-HLH proteins: partners in retinoid-induced myogenesis

et al. 1998

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“…In fact, TT-NPB only repressed at concentrations known to also activate RXR (38,39). In addition, repression was not seen with the RXR␣⌬AF-2 mutant, which should maintain trans-repressive properties if the heterodimeric partner was the operative factor (40). Taken together we conclude that liganded RXR␣ is critical for the observed repressive affect on ANF gene expression.…”

Section: Discussionmentioning

confidence: 60%

Retinoid X Receptor α Represses GATA-4-mediated Transcription via a Retinoid-dependent Interaction with the Cardiac-enriched Repressor FOG-2

Clabby

Robison

Quigley³

et al. 2003

Journal of Biological Chemistry

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Dietary vitamin A and its derivatives, retinoids, regulate cardiac growth and development. To delineate mechanisms involved in retinoid-mediated control of cardiac gene expression, the regulatory effects of the retinoid X receptor ␣ (RXR␣) on atrial naturietic factor (ANF) gene transcription was investigated. The transcriptional activity of an ANF promoter-reporter in rat neonatal ventricular myocytes was repressed by RXR␣ in the presence of 9-cis-RA and by the constitutively active mutant RXR␣F318A indicating that liganded RXR confers the regulatory effect. The RXR␣-mediated repression mapped to the proximal 147 bp of the rat ANF promoter, a region lacking a consensus retinoid response element but containing several known cardiogenic cis elements including a well characterized GATA response element. Glutathione S-transferase "pulldown" assays revealed that RXR␣ interacts directly with GATA-4, in a ligand-independent manner, via the DNA binding domain of RXR␣ and the second zinc finger of GATA-4. Liganded RXR␣ repressed the activity of a heterologous promoter-reporter construct containing GATA-response element recognition sites in cardiac myocytes but not in several other cell types, suggesting that additional cardiac-enriched factors participate in the repression complex. Co-transfection of liganded RXR␣ and the known cardiac-enriched GATA-4 repressor, FOG-2, resulted in additive repression of GATA-4 activity in ventricular myocytes. In addition, RXR␣ was found to bind FOG-2, in a 9-cis-RA-dependent manner. These data reveal a novel mechanism by which retinoids regulate cardiogenic gene expression through direct interaction with GATA-4 and its co-repressor, FOG-2.Retinoids are compounds, derived from vitamin A, which exert pleiotropic effects on cellular differentiation, morphogenesis, and metabolism. The effects of retinoids on cardiac growth and development are well recognized. Offspring of rodents and birds fed a vitamin A-deficient diet display congenital defects involving many organ systems including the cardiovascular system (1, 2). Vitamin A replacement at different stages of embryonic development in these animals actually alters the severity and type of heart defects seen at birth indicating that retinoid signaling pathways play key roles in a variety of developmental programs (1). Similarly, retinaldehyde dehydrogenase-deficient mice die in utero at embryonic day 8 secondary to poor maturation of the ventricular myocardium, an effect that can be rescued by supplementation of maternal vitamin A (3, 4). In addition, retinoids can exert teratogenic effects. Human offspring born of mothers who ingested isotretinoin, a vitamin A analog, during pregnancy exhibited a high incidence of complex cardiac malformations including transposition of the great vessels, tetralogy of Fallot, hypoplastic aortic arch, and ventricular septal defects (5). Moreover, in the developing chick, local application of high concentrations of retinoic acid disrupts the migration of the pre-cardiac mesoderm, an effect that is dose-depe...

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“…We examined whether TSA affects promoter activity of the RAR␤2 gene that had been stably integrated into P19 cells (27). The RAR␤2 promoter contains a canonical RARE and is strongly activated by RA (14,25,30,31). The promoter also contains a cAMP-like responsive element and an auxiliary RARE (CRE and rare, in Fig.…”

Section: Resultsmentioning

confidence: 99%

A histone deacetylase inhibitor potentiates retinoid receptor action in embryonal carcinoma cells

Minucci

Horn

Bhattacharyya

et al. 1997

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

104

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Histone acetylation is thought to have a role in transcription. To gain insight into the role of histone acetylation in retinoid-dependent transcription, we studied the effects of trichostatin A (TSA), a specific inhibitor of histone deacetylase, on P19 embryonal carcinoma cells. We show that coaddition of TSA and retinoic acid (RA) markedly enhances neuronal differentiation in these cells, although TSA alone does not induce differentiation but causes extensive apoptosis. Consistent with the cooperative effect of TSA and RA, coaddition of the two agents synergistically enhanced transcription from stably integrated RA-responsive promoters. The transcriptional synergy by TSA and RA required the RA-responsive element and a functional retinoid X receptor (RXR)͞retinoic acid receptor (RAR) heterodimer, both obligatory for RA-dependent transcription. Furthermore, TSA led to promoter activation by an RXR-selective ligand that was otherwise inactive in transcription. In addition, TSA enhanced transcription from a minimum basal promoter, independently of the RA-responsive element. Finally, we show that TSA alone or in combination with RA increases in vivo endonuclease sensitivity within the RA-responsive promoter, suggesting that TSA treatment might alter a local chromatin environment to enhance RXR͞RAR heterodimer action. Thus, these results indicate that histone acetylation inf luences activity of the heterodimer, which is in line with the observed interaction between the RXR͞RAR heterodimer and a histone acetylase presented elsewhere.

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Retinoid-dependent in vitro transcription mediated by the RXR/RAR heterodimer.

Cited by 65 publications

References 60 publications

Retinoic acid receptors and muscle b-HLH proteins: partners in retinoid-induced myogenesis

Retinoic acid receptors and muscle b-HLH proteins: partners in retinoid-induced myogenesis

Retinoid X Receptor α Represses GATA-4-mediated Transcription via a Retinoid-dependent Interaction with the Cardiac-enriched Repressor FOG-2

A histone deacetylase inhibitor potentiates retinoid receptor action in embryonal carcinoma cells

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