The molecular and genetic dissection of the retinoid signalling pathway

doi:10.1016/0378-1119(93)90069-F

Gene

Volume 135, Issues 1–2, 15 December 1993, Pages 223-228

https://doi.org/10.1016/0378-1119(93)90069-F Get rights and content

Abstract

Retinoids are derivatives of vitamin A (retinol) that exert a wide variety of profound effects on vertebrate development, cellular differentiation and homeostasis. How these simple molecules can exert such pleiotropic effects has recently been an area of intensive investigation. A complex array of combinatorial effects is beginning to emerge from molecular and genetic studies, which may ultimately account for the pleiotropic effects of retinoids.

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Cited by (79)

Vitamin A enrichment: Caution with encapsulation strategies used for food applications
2012, Food Research International
Citation Excerpt :
RA exerts pleiotropic actions through direct interactions with genes via nuclear receptors or through indirect non-genomic actions. Most research work has focused on direct actions and has revealed great complexity in the signaling pathways, especially because RXR can act as a silencing partner for a great number of nuclear receptors (Chambon, 1993, 1996; Tafti & Ghyselinck, 2007; Theodosiou et al., 2010). New areas of research are now emerging because of vitamin A interferences with other nuclear receptors involved in the signaling pathways of vitamins, hormones and/or nutrients.
Vitamin A is essential for life in mammals; it cannot be synthesized de novo and has to be provided by food. Vitamin A is poorly soluble in water and relatively unstable during food processing and storage. Numerous strategies have been developed to avoid its degradation, originally for pharmaceutical uses and now for nutritional applications. Day after day, increasing development of a lot of premixes containing appropriately protected concentrated vitamin A has been used in enriched and functional foods or in food supplements. We present an update of the principal techniques used for vitamin A encapsulation, their advantages and drawbacks and demonstrate that all of these could efficiently protect vitamin A and consequently, increase its bioavailability.
On the other hand, in industrialized countries, vitamin A may be associated with sub-toxic effects due to its accumulation in the liver. Furthermore, it is now generally well agreed that the upper limit intake could be decreased for the elderly despite the known osteoporosis risk in the elderly and the fact that they are known to manifest impaired vitamin A metabolism. In parallel, the new roles of vitamin A in preventive nutrition against neurodegenerative diseases have recently increased the interest in supplementation via functional food or food supplements. This, associated with the increasingly frequent intake of vitamin A in food supplement or enriched food (i.e. with encapsulated vitamin A), leads us to the recommendation that more caution is necessary in the development of food strategies using vitamin A encapsulation, in industrialized countries.
RXRα ablation in epidermal keratinocytes enhances UVR-induced DNA damage, apoptosis, and proliferation of keratinocytes and melanocytes
2011, Journal of Investigative Dermatology
Citation Excerpt :
Paracrine factors, such as endothelins and pro-opiomelanocortin (POMC), which are secreted by keratinocytes and regulate melanocyte proliferation, have been shown to be altered by UVR exposure (Imokawa et al., 1992; Chakraborty et al., 1996; Kadekaro and Abdel-Malek, 2007). Retinoids have been shown to regulate skin development, differentiation, and homeostasis, which are mediated by nuclear receptors such as retinoid acid receptors and retinoid X receptors (RXRs) (Chambon, 1993, 1996). RXRα, the most abundant isoform of RXR in skin, is a central transcriptional regulator in modulating gene expression by heterodimerization with other nuclear receptors (Li et al., 2001).
We show here that keratinocytic nuclear receptor retinoid X receptor-α (RXRα) regulates mouse keratinocyte and melanocyte homeostasis following acute UVR. Keratinocytic RXRα has a protective role in UVR-induced keratinocyte and melanocyte proliferation/differentiation, oxidative stress-mediated DNA damage, and cellular apoptosis. We discovered that keratinocytic RXRα, in a cell-autonomous manner, regulates mitogenic growth responses in skin epidermis through secretion of heparin-binding EGF-like growth factor, GM-CSF, IL-1α, and cyclooxygenase-2 and activation of mitogen-activated protein kinase pathways. We identified altered expression of several keratinocyte-derived mitogenic paracrine growth factors such as endothelin 1, hepatocyte growth factor, α-melanocyte stimulating hormone, stem cell factor, and fibroblast growth factor-2 in skin of mice lacking RXRα in epidermal keratinocytes (RXRα^ep-/- mice), which in a non-cell-autonomous manner modulated melanocyte proliferation and activation after UVR. RXRα^ep-/- mice represent a unique animal model in which UVR induces melanocyte proliferation/activation in both epidermis and dermis. Considered together, the results of our study suggest that RXR antagonists, together with inhibitors of cell proliferation, can be effective in preventing solar UVR-induced photocarcinogenesis.
Cell Cycle Regulatory Effects of Retinoic Acid and Forskolin Are Mediated by the Cyclin C Gene
2009, Journal of Molecular Biology
As a partner of cyclin-dependent kinase (CDK) 3, Cyclin C controls cellular proliferation and, together with CDK8, represses gene transcription. In this study, we showed that the highly expressed Cyclin C gene is a direct target of the nuclear hormone all-trans retinoic acid (RA) in HEK293 human embryonal kidney cells. The RA receptor (RAR) γ associates with a Cyclin C promoter region containing two RAR binding sites. The Cyclin C gene also directly responds to the cAMP activator Forskolin via the transcription factor CREB1 (cAMP response element-binding protein 1), for which we identified four binding sites within the first 2250 bp of its promoter. RARγ and CREB1 show functional convergence via the corepressor NCoR1, which controls in particular the Forskolin response of Cyclin C. The histone deacetylases 1, 5, 6, 7 and 11 are involved in the basal expression of Cyclin C, but in HEK293 and MCF-7 human breast carcinoma cells the antiproliferative effects of the histone deacetylase inhibitor SAHA (suberoylanilide hydroxamic acid) are not mediated by Cyclin C. However, cell cycle progressing effects of all-trans RA and Forskolin are dependent on Cyclin C expression levels. This suggests that the primary regulation of Cyclin C by all-trans RA and Forskolin mediates some of the cell cycle control actions of these compounds.
Regulation of the hyaluronan synthase 2 gene by convergence in cyclic AMP response element-binding protein and retinoid acid receptor signaling
2009, Journal of Biological Chemistry
The human hyaluronan synthase 2 (HAS2) gene encodes for an enzyme making hyaluronan, altered concentrations of which are associated with many pathological situations including wounding, several inflammatory conditions, and malignant tumors. In this study we showed that HAS2 is a primary target of the cAMP activator forskolin and the nuclear hormone all-trans-retinoic acid (RA). The first 2250 bp of the promoter contain three response elements (REs) for the transcription factor CREB1 as well as two REs for the nuclear receptor RAR. Chromatin immunoprecipitation and re-chromatin immunoprecipitation assays using selected fragments of the promoter containing the putative REs showed that forskolin and all-trans-RA modulate the formation of complexes between CREB1 and RAR with various co-regulators at the predicted sites. Interestingly, CREB1 complexes are regulated by all-trans-RA as are RAR complexes by forskolin. Reporter gene assays using nested promoter fragments supported these findings. Forskolin and all-trans-RA co-stimulation reduced the binding of CREB1, RAR, and the co-repressor nuclear receptor co-repressor 1 (NCoR1), but enhanced the association of co-activators MED1 and CREB-binding protein (CBP). RNA interference experiments suggested that MED1 and NCoR1 are central for the all-trans-RA induction of the HAS2 gene and CBP dominates its forskolin response. In general, our findings suggest a convergence of CREB1 and RAR signaling, and demonstrate the individual character of each RE in terms of co-regulator use.
Cellular retinoic acid-binding protein II gene expression is directly induced by estrogen, but not retinoic acid, in rat uterus
2003, Journal of Biological Chemistry
It has been suggested that cellular retinoic acid-binding protein (II) (CRABP(II)) may have a role in the movement of retinoic acid (RA) to its nuclear receptors, thereby enhancing the action of RA in the cells in which it is expressed. RA has also been shown to increase expression of CRABP(II). Previous work from our laboratory has shown that 17β-estradiol (E₂) administration to prepubertal female rats leads to acquisition of the ability of the lining epithelium to synthesize RA as well as to express CRABP(II). To determine whether this appearance of CRABP(II) was dependent on the production of RA, both E₂ and RA were administered to ovariectomized rats. E₂ administration induced expression of the CRABP(II) gene in the uterus within 4 h, and this induction was not inhibited by prior administration of puromycin, indicating that the induction was direct. In contrast, RA caused no change in CRABP(II) message level, even at times as late as 48 h after administration. Isolation and analysis of 4.5 kb of the 5′-flanking region of the gene revealed no apparent E₂-response element. Using this portion of the gene to drive expression of the luciferase gene in transfected cells allowed identification of a region containing an imperfect estrogen-response element and estrogen-response element half-site, necessary for E₂-driven induction. A possible Sp1 binding site in the 5′-flanking region of the CRABP(II) gene was also required for this induction. The ability of E₂ to induce expression of CRABP(II) suggests that it can enhance the activity of RA, directly affecting expression of retinoid-responsive genes.
Up-regulation of acid sphingomyelinase during retinoic acid-induced myeloid differentiation of NB4, a human acute promyelocytic leukemia cell line
2002, Journal of Biological Chemistry
All-trans-retinoic acid (ATRA) induces myeloid differentiation of a human promyelocytic leukemia cell line, NB4, but does not affect its subclone NB4/RA harboring a point-mutated ligand-binding domain (AF2) in retinoic acid receptor α (RARα) gene. We found that ATRA induced the 4-fold elevation of acid sphingomyelinase (ASMase) activity 24 h after treatment in NB4 cells, but not in NB4/RA cells. ATRA did not affect neutral sphingomyelinase activity in either NB4 or NB4/RA. Upon treatment with ATRA, ceramide, the product of an ASMase reaction, accumulated in NB4 cells. Northern blot analysis showed a marked elevation of the ASMase mRNA 8 h after ATRA treatment, reaching a plateau at 24 h. Regulation ofASMase gene expression was studied by a promoter analysis using luciferase reporter assay. The 5′-upstream flanking region of human ASMase gene (−519/+300) conjugated with theluciferase gene was introduced into COS-7 cells. Luciferase activity in transformed cells markedly increased in response to ATRA stimulation when the wild type RARα or the PML/RARα hybrid protein was co-expressed. Deletion experiments revealed that a short sequence at the 5′-end (−519/−485) was indispensable for the ATRA response. Within this short region, two retinoic acid-responsive element-like motifs (TGCCCG and TCTCCT) and one AP2-like motif (CCCTTCCC) were identified. Deletion and base-substitution experiments showed that all three motifs are required for the full expression induced by ATRA. Electrophoresis mobility shift assays with the nuclear extract of ATRA-treated NB4 cells showed that proteins were bound specifically to the probe being mediated by all three motifs in the promoter sequence.

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^☆: Presented at the COGENE Symposium, ‘From the Double Helix to the Human Genome: 40 Years of Molecular Genetics’, UNESCO, Paris, 21–23 April 1993.

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The molecular and genetic dissection of the retinoid signalling pathway☆

Abstract

Cell

Trends Biochem. Sci.

Curr. Topics Dev. Biol.

Cell

Cell

Cell

Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids

Altering the genome by homologous recombination

Science

Exogenous retinoic acid rapidly induces anterior ectopic expression of murine Hox-2 genes in vivo

Development

Differential expression of genes encoding a, β and γ retinoic acid receptors and CRABP in the developing limbs of the mouse

Nature

Retinoic acid receptors and cellular retinoid binding proteins.I. A systematic study of their differential pattern of transcription during mouse organogenesis

Development

Identification of a receptor for the morphogen retinoic acid

Nature

Histology of the lesions produced in the reproductive tract of animals fed a diet deficient in vitamin A alcohol but containing vitamin A acid I. The male rat

J. Reprod. Fertil.

Murine isoforms of retinoic acid receptor y with specific patterns of expression

The role of nuclear retinoic acid receptors in the regulation of gene expression

Respecification of vertebral identities by retinoic acid

Development

On the probability of fixation of mutant genes in a population

Genetics

Induction mechanism of a single gene molecule: stochastic or deterministic?

BioEssays

Multiple isoforms of the mouse retinoic acid receptor a are generated by alternative splicing and differential induction by retinoic acid

EMBO J.