Endogenous retinoid X receptors can function as hormone receptors in pituitary cells.

Davis, K D; Berrodin, T J; Stelmach, J E; Winkler, J D; Lazar, Mitchell A.

doi:10.1128/mcb.14.11.7105

Cited by 39 publications

(33 citation statements)

References 53 publications

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“…RXR␣-null F9 embryonal carcinoma cells are resistant to retinoid-mediated cellular differentiation, anti-proliferation, and apoptosis (14). Similarly, RXR ligand demonstrates growth inhibitory effects in multiple cancer cell lines (15)(16)(17). Together, these findings suggest a role for RXR in tumor pathogenesis and the potential use of RXR ligand in cancer therapy.…”

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confidence: 70%

p21WAF1/CIP1 Is a Common Transcriptional Target of Retinoid Receptors

Tanaka

Suh

et al. 2007

Journal of Biological Chemistry

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The divergent response and the molecular mechanisms underlying the anti-cancer effects of retinoid X receptor (RXR) ligand (rexinoid) therapy are poorly understood. This study demonstrates that ligand-activated RXR homodimer facilitated G 1 arrest by up-regulation of p21 in vitro and in vivo but failed to induce G 1 arrest when p21 expression was blocked by p21 small interfering RNA. RXR ligand-dependent p21 up-regulation was transcriptionally controlled through the direct binding of RXR homodimers to two consecutive retinoid X response elements in the p21 promoter. Structural overlap of a retinoic acid response element with these retinoid X response elements led to a high affinity binding of retinoic acid receptor/RXR heterodimer to the retinoic acid response element, resulting in the prevention of RXR ligand-mediated p21 transactivation. These data show that p21 is a potential and novel molecular target for RXR ligandmediated anti-cancer therapy and that the expression level of retinoic acid receptor and RXR in tumors may be crucial to induce p21-mediated cell growth arrest in RXR ligand therapy.Retinoids are natural and synthetic vitamin A derivatives that regulate a multitude of biological processes in mammalian cells, including metabolism, development, cell proliferation, differentiation, and carcinogenesis (1). Carcinogen exposure causes squamous metaplasia of tracheal and other epithelia, and administration of vitamin A prevents tumor formation (2). Retinoids are clinically used to target selected human cancers (3,27). The actions of retinoids are mediated by two distinct classes of retinoid receptors, retinoic acid receptors (RAR␣, -␤, and -␥) 3 and retinoid X receptors (RXR␣, ␤, and ␥), which require all-trans-retinoic acid and 9-cis-retinoic acid, respectively, for transcriptional activation. RXR is a combinatorial partner in the nuclear receptor family that forms homo-or heterodimers with a variety of hormone and orphan receptors, including RAR, vitamin D receptor, thyroid hormone receptor (TR), peroxisome proliferator-activated receptor (PPAR), chicken ovalbumin upstream promoter transcription factor (COUP-TF), and other receptors (4). The dimeric receptors bind to specific DNA response element of target genes, and this DNA binding specificity is determined by the number of spacer nucleotides present between the two direct repeats of the canonical binding sequence AGGTCA (5). For instance, RAR and RXR heterodimer binds to retinoic acid response element (RARE) that contains two or five spacers (DR2 or -5), and RXR homodimer binds to retinoid X response element (RXRE) in which the half-sites are separated by a single nucleotide (DR1) (5). Direct binding of ligands to the receptors is required for transcriptional activation, and in the absence of ligands, this activation is blocked by binding of specific repressors to the receptors (6). Ligand binding triggers a release of the repressors from the complex and promotes interaction with co-activator complexes that forms a bridge between the nuclear recepto...

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confidence: 70%

p21WAF1/CIP1 Is a Common Transcriptional Target of Retinoid Receptors

Tanaka

Suh

et al. 2007

Journal of Biological Chemistry

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“…Despite the uncertainties, which require further investigation, several reports propose that ligandinduced RXR homodimers regulate expression of retinoid target genes. These include hRXR␥ (35), rGH (48), hApoA-I (33), hApoA-II (34), among others (5,6). We note that none of these genes has a direct role in embryonic pattern formation; they are instead involved in retinoid autoregulation, growth, and metabolism.…”

Section: Discussionmentioning

confidence: 99%

Metabolism to a response pathway selective retinoid ligand during axial pattern formation

Pijnappel

Folkers²,

Jonge³

et al. 1998

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

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We report identification of 9-cis-4-oxo-retinoic acid (9-cis-4-oxo-RA) as an in vivo retinoid metabolite in Xenopus embryos. 9-Cis-4-oxo-RA bound receptors (RARs) ␣, ␤, and ␥ as well as retinoid X receptors (RXRs) ␣, ␤, and ␥ in vitro. However, this retinoid displayed differential RXR activation depending on the response pathway used. Although it failed to activate RXRs in RXR homodimers, it activated RXRs and RARs synergistically in RAR-RXR heterodimers. 9-Cis-4-oxo-RA thus acted as a dimer-specific agonist. Considering that RAR-RXR heterodimers are major functional units involved in transducing retinoid signals during embryogenesis and that 9-cis-4-oxo-RA displayed high potency for modulating axial pattern formation in Xenopus, metabolism to 9-cis-4-oxo-RA may provide a mechanism to target retinoid action to this and other RAR-RXR heterodimer-mediated processes.Much evidence implicates retinoids (vitamin A and metabolites) in regulating embryonic pattern formation as well as growth, differentiation, reproduction, metabolism, and homeostasis (1-4). Many important effects of retinoids are mediated by two families of nuclear receptors: retinoic acid (RA) receptors (RARs) and retinoid X receptor (RXRs), each consisting of three types (␣, ␤, and ␥), there being several isoforms of each type (5-7). RARs and RXRs are retinoid ligand-dependent transcription factors, which can act via specific DNA response elements consisting of direct repeats of the hexameric motif RG(G͞ T)TCA. Two main retinoid response pathways are known. RARs and RXRs heterodimerize and then activate transcription via RA response elements consisting of direct repeats (DRs) spaced by 2 (DR-2) or 5 (DR-5) base pairs. Both the RAR and RXR partners of the heterodimer can be ligand activated in vivo, resulting in synergistic activation (8-13). RXRs also homodimerize, and this homodimerization contrasts with RAR-RXR heterodimerization in being ligand stimulated (14-17). RXR homodimers activate transcription from retinoid X response elements (RXREs) consisting of DRs spaced by 1 (DR-1) base pair. In addition to these two main pathways, retinoid receptors interact with other signaling pathways, either via heterodimerization between RXR and other nuclear hormone receptors or via crosstalk with AP-1.Paralleling the multiplicity of retinoid receptors, several natural retinoids are known to act as retinoid receptor ligands (4, 18-23). These fall into two groups. Ligands that activate RARs only include all-trans-RA, all-trans-3,4-didehydroretinoic acid (ddRA), all-trans-4-oxo-retinoic acid (4-oxo-RA), all-trans-4-oxoretinal, and all-trans-4-oxo-retinol. These ligands activate only RAR-RXR heterodimers and act via the RAR part of the heterodimer. The second group, including 9-cis-RA and 9-cis-3,4-didehydroretinoic acid, activates both RARs and RXRs. 9-Cis-RA has been shown to activate RAR-RXR heterodimers more efficiently than natural RAR ligands, suggesting that both partners of the heterodimer are activated by this ligand (8, 12). 9-Cis-RA also activat...

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“…4, lanes 1-4) to ensure that LG100268 was acting as an RXR-selective ligand in vivo in our system, Northern analysis was performed on the RAR␤ gene product. RAR␤ transcripts have been shown to be up-regulated by ligands that bind to RAR, but not by RXR-selective compounds, in F9 cells (8). Fig.…”

Section: Retinoids Induce 24-(oh)ase In Vivo 23907mentioning

confidence: 99%

“…However, these genes have not been shown to be regulated by retinoids in vivo. While another gene product (growth hormone) has been shown to increase in cultured cells treated with RXR-and RAR-selective ligands (8), there are currently no known biological target genes of RXR in the intact animal.…”

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confidence: 99%

Retinoid X Receptor Acts as a Hormone Receptor in Vivo to Induce a Key Metabolic Enzyme for 1,25-Dihydroxyvitamin D3

Allegretto¹,

Shevde²,

Zou³

et al. 1995

Journal of Biological Chemistry

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We demonstrate here that RNA levels of 25-hydroxyvitamin D 3 -24-hydroxylase (24-(OH)ase), a key catabolic enzyme for 1,25-dihydroxyvitamin D 3 , are increased by a highly selective retinoid X receptor (RXR) ligand, LG100268, in mice within hours. Correspondingly, upon LG100268 treatment, kidney 24-(OH)ase enzymatic activity increases 5-10-fold. The endogenous retinoid hormones, all-trans-retinoic acid and 9-cis-retinoic acid, and the synthetic retinoic acid receptor-selective compound, TTNPB, also stimulate 24-(OH)ase. Additionally, we show that LG100268 stimulates transcription of a luciferase reporter plasmid driven by 24-(OH)ase promoter sequences in the presence of RXR in CV-1 cell cotransactivation assays. This first demonstration of a gene that is regulated in the intact animal through an RXR-mediated pathway confirms earlier hypotheses that RXR is a bona fide hormone receptor. Regulation of a key gene in the vitamin D signaling pathway by a retinoid transducer may provide a molecular basis for some of the documented biological effects of vitamin A on bone and vitamin D metabolism. Retinoic acid receptors (RARs)1 have been shown to act as hormone receptors by virtue of the fact that they bind all-transretinoic acid (tRA) with high affinity and activate target genes in the presence of tRA in cell-based cotransactivation assays and in vivo (reviewed in Ref. 1). Retinoid X receptors (RXRs) are also thought to act as hormone receptors (reviewed in Ref. 1) since they bind 9-cis-retinoic acid (9cRA) with high affinity (2, 3) and have been shown to stimulate transcription from distinct elements known as RXR-responsive elements in promoter sequences of the apolipoprotein A1 (apoA1) and cellular retinol-binding protein II (CRBPII) genes in cell-based cotransactivation assays in response to 9cRA (2, 3), tRA (4, 5), or RXR-selective ligands (6, 7). However, these genes have not been shown to be regulated by retinoids in vivo. While another gene product (growth hormone) has been shown to increase in cultured cells treated with RXR-and RAR-selective ligands (8), there are currently no known biological target genes of RXR in the intact animal.RXRs are thought to form homodimers upon interaction with ligand (1) to activate putative RXR-selective genes, such as CRBPII and apoA1, through RXR-responsive elements in the promoters of those genes (2-7). RXR is also known to participate in heterodimers with a number of other intracellular receptors, including the vitamin D receptor (VDR), RAR, or thyroid hormone receptor to activate a variety of target genes, which are stimulated by 1,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ), tRA, or thyroid hormone, respectively (1). RXR is thought to act as a silent partner in these interactions, although the effects of liganding of RXR under these circumstances have not been thoroughly explored. Additionally, recent studies describe instances of stimulation of gene transcription by hormone-occupied RXR interacting with a supposedly unoccupied orphan receptor (9, 10).To study the consequen...

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Endogenous retinoid X receptors can function as hormone receptors in pituitary cells.

Cited by 39 publications

References 53 publications

p21WAF1/CIP1 Is a Common Transcriptional Target of Retinoid Receptors

p21WAF1/CIP1 Is a Common Transcriptional Target of Retinoid Receptors

Metabolism to a response pathway selective retinoid ligand during axial pattern formation

Retinoid X Receptor Acts as a Hormone Receptor in Vivo to Induce a Key Metabolic Enzyme for 1,25-Dihydroxyvitamin D3

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