Retinoic Acid Actions through Mammalian Nuclear Receptors

Huang, Peiying; Chandra, Vikas; Rastinejad, Fraydoon

doi:10.1021/cr400161b

Cited by 123 publications

(123 citation statements)

References 328 publications

(825 reference statements)

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“…DNA motifs for RAR-RXR binding (known as retinoic acid response elements [RARE]) are typically direct repeats of half sites puG(G/T)TCA separated by 2 or 5 nucleotides. RA binding to RAR-RXR (and related heterodimeric receptors) can have profound effects on immune cell development, activation, homing, and function (5,(12)(13)(14).Vitamin D can be synthesized by the body in addition to being obtained through dietary sources. Cholecalciferol (vitamin D 3 ) and ergocalciferol (vitamin D 2 ) are acquired through the diet, but cholecalciferol is also produced photochemically from 7-dehydrocholesterol in the skin.…”

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“…Once converted from retinal, RA in the form of all-trans-RA can be spontaneously isomerized to 9-cis-RA. The two metabolites function as high-affinity ligands, respectively, for the retinoic acid receptor (RAR) and retinoid X receptor (RXR) proteins (11,12). RAR and RXR are members of the nuclear receptor superfamily.…”

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Vitamin Supplementation at the Time of Immunization with a Cold-Adapted Influenza Virus Vaccine Corrects Poor Mucosal Antibody Responses in Mice Deficient for Vitamins A and D

Surman

Penkert

Jones

et al. 2016

Clin Vaccine Immunol

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V itamin A deficiencies (VAD) and vitamin D deficiencies (VDD) have long been considered maladies in the developing world, but recent research demonstrates that children and adults of developed countries also suffer from vitamin deficits (1-4). Individuals with low vitamin levels are particularly vulnerable to infections of the gastrointestinal and respiratory tracts (5-8), the latter of which are responsible for one-fifth of all deaths among children under the age of five (1, 9).Vitamin A is ingested in the form of retinyl esters or betacarotene. It is stored in the liver as an ester and is transported through the circulatory system as retinol bound to the retinol binding protein (RBP) (10). Upon cellular uptake, retinol is converted to retinal by ubiquitous alcohol dehydrogenases, but further conversion to retinoic acid (RA), an active metabolite of vitamin A, requires specialized aldehyde dehydrogenases (ALDH1A). ALDH1A enzymes are expressed by a subset of cells, including gut dendritic cells and epithelial cells lining the upper and lower respiratory tracts (URT and LRT) (5, 8). Once converted from retinal, RA in the form of all-trans-RA can be spontaneously isomerized to 9-cis-RA. The two metabolites function as high-affinity ligands, respectively, for the retinoic acid receptor (RAR) and retinoid X receptor (RXR) proteins (11, 12). RAR and RXR are members of the nuclear receptor superfamily. These exist as monomers, homodimers, and heterodimers. DNA motifs for RAR-RXR binding (known as retinoic acid response elements [RARE]) are typically direct repeats of half sites puG(G/T)TCA separated by 2 or 5 nucleotides. RA binding to RAR-RXR (and related heterodimeric receptors) can have profound effects on immune cell development, activation, homing, and function (5,(12)(13)(14).Vitamin D can be synthesized by the body in addition to being obtained through dietary sources. Cholecalciferol (vitamin D 3 ) and ergocalciferol (vitamin D 2 ) are acquired through the diet, but cholecalciferol is also produced photochemically from 7-dehydrocholesterol in the skin. Cholecalciferol is con- Vitamin A and D metabolites are highly interactive. Calcitriol binds the vitamin D receptor (VDR), which like RAR can heterodimerize with RXR (17). The same DNA binding motifs described for RAR-RXR [puG(G/T)TCA] can be recognized by the VDR-RXR complex, but half sites are often separated by 3 nucleotides (17) rather than 2 or 5. Receptor proteins can bind promiscuously to ligands and to noncanonical DNA motifs. In some instances, vitamin receptors (and related members of the nuclear receptor superfamily) behave synergistically, but in other instances, they antagonize one another (e.g., vitamin D exerts a negative effect on the vitamin A-dependent commitment of bone marrow cells to the granulocytic lineage [13,[17][18][19][20]

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Vitamin Supplementation at the Time of Immunization with a Cold-Adapted Influenza Virus Vaccine Corrects Poor Mucosal Antibody Responses in Mice Deficient for Vitamins A and D

Surman

Penkert

Jones

et al. 2016

Clin Vaccine Immunol

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“…1 Retinoid X ligands (e.g., 9-cis retinoic acid, Figure 1) are small lipophilic hormones, which, when bound to a heterodimeric or a homodimeric (i.e., RXR-RXR fusion) receptor, cause it to bind a transcription complex on DNA and to promote expression of target genes. RXRs are found ubiquitously and differentially in mammalian cells, including in both glial and neuronal brain tissue.…”

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Synthesis of [¹¹C]Bexarotene by Cu-Mediated [¹¹C]Carbon Dioxide Fixation and Preliminary PET Imaging

Rotstein

Hooker

Woo

et al. 2014

ACS Med. Chem. Lett.

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Bexarotene (Targretin) is a retinoid X receptor (RXR) agonist that has applications for treatment of T cell lymphoma and proposed mechanisms of action in Alzheimer's disease that have been the subject of recent controversy. Carbon-11 labeled bexarotene ([ 11 Ccarbonyl]4- [1-(3,5,5,8,8-pentamethyltetralin-2-yl)ethenyl]benzoic acid) was synthesized using a Cu-mediated cross-coupling reaction employing an arylboronate precursor 1 and [ 11 C]carbon dioxide under atmospheric pressure in 15 ± 2% uncorrected radiochemical yield (n = 3), based on [ 11 C]CO 2 . Judicious choice of solvents, catalysts, and additives, as well as precursor concentration and purity of [ 11 C]CO 2 , enabled the preparation of this 11 C-labeled carboxylic acid. Formulated [ 11 C]bexarotene was isolated (>37 mCi) with >99% radiochemical purity in 32 min. Preliminary positron emission tomography−magnetic resonance imaging revealed rapid brain uptake in nonhuman primate in the first 75 s following intravenous administration of the radiotracer (specific activity >0.3 Ci/μmol at time of injection), followed by slow clearance (Δ = −43%) over 60 min. Modest uptake (SUV max = 0.8) was observed in whole brain and regions with high RXR expression. KEYWORDS: Bexarotene, targretin, positron emission tomography, carbon-11, carbon dioxide fixation, retinoid X receptor, Alzheimer's disease R etinoid X receptors (RXRs) function as key transcription factors inasmuch as they are the heterodimeric partners for most nuclear receptors, including retinoic acid receptors (RARs), peroxisome proliferator-activated receptors (PPARs), vitamin D receptor, and thyroid hormone receptor. 1 Retinoid X ligands (e.g., 9-cis retinoic acid, Figure 1) are small lipophilic hormones, which, when bound to a heterodimeric or a homodimeric (i.e., RXR-RXR fusion) receptor, cause it to bind a transcription complex on DNA and to promote expression of target genes. RXRs are found ubiquitously and differentially in mammalian cells, including in both glial and neuronal brain tissue. 2 Defective retinoid signaling and deficiency of apolipoprotein E (ApoE) are closely associated with Alzheimer's disease (AD). 3 Bexarotene (4-[1-(3,5,5,8,8-pentamethyltetralin-2-yl)ethenyl]benzoic acid, Figure 1), an FDA-approved selective RXR agonist, 4 has recently been demonstrated to induce clearance of β-amyloid from the brains of murine AD models through activation of the APOE gene, which is the most indicative genetic risk factor for late-onset AD. 5 In vitro and in vivo studies also suggest that bexarotene is acting on RXRs, and not directly on β-amyloid or by compromising the blood−brain barrier. 6 A transgenic mouse model of AD (Tg2576) exhibited reversal of cognitive and behavioral degradation with the administration of bexarotene. 5 These findings have proven to be controversial, however, as several laboratories have struggled to reproduce both the scope and magnitude of the in vivo results. 7−11 An additional caveat to these results is that the bexarotene dose used to achieve these effect...

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“…difficulties in drug development and toxicity, as well as, the continued focus on the identification of natural ligands [10]. For example, the role of retinoid X receptors (RXRs) as heterodimeric partners of several members of the nuclear receptor family, including retinoic acid receptor (RAR), makes them promising drug targets; however, controversy still surrounds whether or not 9-cis-retinoic acid is its true endogenous ligand [11].…”

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Orphan nuclear receptors as drug targets for the treatment of prostate and breast cancers

Roshan-Moniri

Hsing

Butler

et al. 2014

Cancer Treatment Reviews

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Retinoic Acid Actions through Mammalian Nuclear Receptors

Cited by 123 publications

References 328 publications

Vitamin Supplementation at the Time of Immunization with a Cold-Adapted Influenza Virus Vaccine Corrects Poor Mucosal Antibody Responses in Mice Deficient for Vitamins A and D

Vitamin Supplementation at the Time of Immunization with a Cold-Adapted Influenza Virus Vaccine Corrects Poor Mucosal Antibody Responses in Mice Deficient for Vitamins A and D

Synthesis of [¹¹C]Bexarotene by Cu-Mediated [¹¹C]Carbon Dioxide Fixation and Preliminary PET Imaging

Orphan nuclear receptors as drug targets for the treatment of prostate and breast cancers

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Retinoic Acid Actions through Mammalian Nuclear Receptors

Cited by 123 publications

References 328 publications

Vitamin Supplementation at the Time of Immunization with a Cold-Adapted Influenza Virus Vaccine Corrects Poor Mucosal Antibody Responses in Mice Deficient for Vitamins A and D

Vitamin Supplementation at the Time of Immunization with a Cold-Adapted Influenza Virus Vaccine Corrects Poor Mucosal Antibody Responses in Mice Deficient for Vitamins A and D

Synthesis of [11C]Bexarotene by Cu-Mediated [11C]Carbon Dioxide Fixation and Preliminary PET Imaging

Orphan nuclear receptors as drug targets for the treatment of prostate and breast cancers

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Synthesis of [¹¹C]Bexarotene by Cu-Mediated [¹¹C]Carbon Dioxide Fixation and Preliminary PET Imaging