Characterization of the chimeric retinoic acid receptor RARα/VDR

Pemrick, Suzanne M.; Abarzúa, P; Kratzeisen, C; Marks, Michael S.; Medin, Jeffrey A.; Ozato, K; Grippo, Joseph F.

doi:10.1038/sj.leu.2400937

Cited by 14 publications

(14 citation statements)

References 57 publications

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“…It is known that the RXRs (Barsony & Prufer 2002), and under some circumstances, the RARs (Pemrick et al 1998), can bind with the VDR to activate or repress corresponding DNA response elements. Since the purified VDR only formed a weakly detectable complex (Fig.…”

Section: Characterization Of a Vdre In The Egfr Promoter · Kenneth Rmentioning

confidence: 99%

Identification and characterization of a response element in the EGFR promoter that mediates transcriptional repression by 1,25-dihydroxyvitamin D3 in breast cancer cells

McGaffin

Chrysogelos²

2005

Journal of Molecular Endocrinology

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Reduction of epidermal growth factor receptor (EGFR) mRNA and protein by 1,25-dihydroxyvitamin D3 has been documented in MCF7, T47D, and BT549 breast cancer cells. In the present report, functional mapping of the EGFR promoter in BT549 cells has revealed a sequence of DNA between nucleotide positions −536 and −478 that resembles a consensus vitamin D response element (VDRE) and confers a vitamin D response upon both the homologous and a minimal heterologous promoter. In vitro footprinting and gel shift assays demonstrate the presence of an unidentified nuclear factor that is required for strong binding of the vitamin D receptor (VDR) to this putative VDRE. An Sp1 binding site was also identified in close proximity and shown to bind Sp1 from nuclear extract. Mutational analysis and functional studies using a minimal heterologous promoter provide evidence that the VDR in concert with an unknown nuclear partner mediates basal EGFR repression through displacement of Sp1 which is augmented in the presence of a ligand.

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Section: Characterization Of a Vdre In The Egfr Promoter · Kenneth Rmentioning

confidence: 99%

Identification and characterization of a response element in the EGFR promoter that mediates transcriptional repression by 1,25-dihydroxyvitamin D3 in breast cancer cells

McGaffin

Chrysogelos²

2005

Journal of Molecular Endocrinology

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“…Biological activity of retinol occurs through oxidative conversion to all-trans retinoic acid (retinoic acid) (2). Retinoic acid is a ligand for nuclear retinoic acid receptors (RAR-␣, -␤, -␥) that bind to gene response elements and thereby regulate gene transcription (3). Most actions of retinoic acid are believed to be mediated through activation of RARs (4).…”

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confidence: 99%

Auto-regulation of Retinoic Acid Biosynthesis through Regulation of Retinol Esterification in Human Keratinocytes

Kurlandsky

Duell

Kang

et al. 1996

Journal of Biological Chemistry

131

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In this report, we describe an auto-regulatory loop in human keratinocytes, whereby all-trans retinoic acid (retinoic acid) regulates its own biosynthesis from all-trans retinol (retinol) through regulation of retinol esterification. Retinol esterification activity was low in normal proliferating human keratinocytes, cultured in retinoid-free media. Treatment of keratinocytes with retinoic acid induced retinol esterifying activity (8-fold). Induction of retinol esterifying activity was blocked by either actinomycin D or cycloheximide. Based on substrate specificity and inhibitor sensitivity, lecithin:retinol acyltransferase (LRAT) was identified as the retinoic acid-inducible retinol esterifying enzyme. Induction of LRAT by retinoic acid reduced conversion of retinol to retinoic acid by 50%. This reduction in retinoic acid synthesis resulted from sequestration of retinol as retinyl esters, since inhibition of LRAT restored retinoic acid synthesis to control levels. In normal human skin, undifferentiated keratinocytes, in the lowest cell layer, esterified retinol 4 times greater, than differentiating keratinocytes, in upper cell layers, reflecting an induced state, under conditions of retinol sufficiency. Regulation of LRAT activity by retinoic acid provides a novel mechanism through which retinoic acid can regulate its own level by controlling availability of retinol for conversion to retinoic acid. In human skin in vivo, retinyl esters synthesized in basal keratinocytes could undergo hydrolysis during differentiation and thus serve as a source of retinol for keratinocytes in upper layers of skin.

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“…All these nuclear receptors share several well-characterized structural domains, including a conserved DNA-binding domain, and a ligand-binding domain at the carboxyl terminus of the receptor (Pemrick et al, 1994;Kumar and Thompson, 1999). Nuclear retinoic acid receptors, the retinoic acid receptor (RAR), and retinoic X receptor (RXR) classes, are each composed of a, b, and g subtypes with more than one isoform for each receptor subtype (Chambon, 1996).…”

Section: Introductionmentioning

confidence: 99%

Retinoic acid receptors interfere with the TGF-β/Smad signaling pathway in a ligand-specific manner

et al. 2003

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Transforming growth factor-b (TGF-b) and retinoic acid (RA) are important regulators of cell growth and differentiation. The TGF-b receptors utilize Smad proteins to transduce signals intracellularly and regulate transcription of target genes, either directly or in combination with other sequence-specific transcription factors. Two classes of nuclear receptors, the retinoic acid receptors (RARs) and the retinoic X receptors, are involved in mediating transcriptional responses to RA. Given the known interactions between the TGF-b and RAR pathways, we have investigated the role played by RAR ligands in modulating functional interactions between Smad3 and RARs. Using transient cell transfection experiments with an artificial Smad3/Smad4-dependent reporter construct, we demonstrate that RAR overexpression enhances Smad-driven transactivation, an effect that requires both Smad3 and Smad4. We provide evidence that RAR effect on Smad3/Smad4-driven transcription is prevented by natural and synthetic RAR agonists, and potentiated by synthetic RAR antagonists. The activity of two TGF-b-responsive human gene promoter constructs was regulated in a parallel fashion. Using both mammalian two-hybrid and immunoprecipitation/Western methods, we demonstrate a direct interaction between the region DEF of RARc and the MH2 domain of Smad3, inhibited by RAR agonists and enhanced by their antagonists. We propose that RARs may function as coactivators of the Smad pathway in the absence of RAR agonists or in the presence of their antagonists, a phenomenon that contrasts with their known role as agonist-activated transcriptional regulators of RA-dependent genes.

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Characterization of the chimeric retinoic acid receptor RARα/VDR

Cited by 14 publications

References 57 publications

Identification and characterization of a response element in the EGFR promoter that mediates transcriptional repression by 1,25-dihydroxyvitamin D3 in breast cancer cells

Identification and characterization of a response element in the EGFR promoter that mediates transcriptional repression by 1,25-dihydroxyvitamin D3 in breast cancer cells

Auto-regulation of Retinoic Acid Biosynthesis through Regulation of Retinol Esterification in Human Keratinocytes

Retinoic acid receptors interfere with the TGF-β/Smad signaling pathway in a ligand-specific manner

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