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PubMed2004

Synergistic effects of acyclic retinoid and OSI-461 on growth inhibition and gene expression in human hepatoma cells.

Hepatoma is one of the most frequently occurring cancers worldwide. However, effective chemotherapeutic agents for this disease have not been developed. Acyclic retinoid, a novel synthetic retinoid, can reduce the incidence of postsurgical recurrence of hepatoma and improve the survival rate. OSI-461, a potent derivative of exisulind, can increase intracellular levels of cyclic GMP, which leads to activation of protein kinase G and induction of apoptosis in cancer cells. In the present study, we examined the combined effects of acyclic retinoid plus OSI-461 in the HepG2 human hepatoma cell line. We found that the combination of as little as 1.0 micromol/L acyclic retinoid and 0.01 micromol/L OSI-461 exerted synergistic inhibition of the growth of HepG2 cells. Combined treatment with low concentrations of these two agents also acted synergistically to induce apoptosis in HepG2 cells through induction of Bax and Apaf-1, reduction of Bcl-2 and Bcl-xL, and activation of caspase-3, -8, and -9. OSI-461 enhanced the G0-G1 arrest caused by acyclic retinoid, and the combination of these agents caused a synergistic decrease in the levels of expression of cyclin D1 protein and mRNA, inhibited cyclin D1 promoter activity, decreased the level of hyperphosphorylated forms of the Rb protein, induced increased cellular levels of the p21(CIP1) protein and mRNA, and stimulated p21(CIP1) promoter activity. Moreover, OSI-461 enhanced the ability of acyclic retinoid to induce increased cellular levels of retinoic acid receptor beta and to stimulate retinoic acid response element-chloramphenicol acetyltransferase activity. A hypothetical model involving concerted effects on p21(CIP1) and retinoic acid receptor beta expression is proposed to explain these synergistic effects. Our results suggest that the combination of acyclic retinoid plus OSI-461 might be an effective regimen for the chemoprevention and chemotherapy of human hepatoma and possibly other malignancies.

Antineoplastic Agents↗
PubMed2003

A neuronal-specific differentiation protein that directly modulates retinoid receptor transcriptional activation.

BACKGROUND: The specificity of a nuclear receptor's ability to modulate gene expression resides in its ability to bind a specific lipophilic ligand, associate with specific dimerization partners and bind specific DNA sequences in the promoter regions of genes. This sequence of events appears to be the basis for targeting an additional regulatory complex composed of a variety of protein and RNA components that deliver signals for facilitation or inhibition of the RNA polymerase complex. Characterization of the tissue and cell-specific components of these coregulatory complexes appear to be integral to our understanding of nuclear receptor regulation of transcription. RESULTS: A novel yeast screen sensitive to retinoid-X receptor (RXR) transcriptional activation resulted in the isolation of the rat homologue of the mouse NPDC-1 gene. NPDC-1 has been shown to be involved in the control of neural cell proliferation and differentiation, possibly through interactions with the cell cycle promoting transcription factor E2F-1. Although the amino acid sequence of NPDC-1 is highly conserved between mouse, rat and human homologues, their tissue specific expression was seen to vary. A potential for direct protein:protein interaction between NPDC-1, RXR and retinoic acid receptor beta (RARbeta) was observed in vitro and NPDC-1 facilitated RXR homodimer and RAR-RXR heterodimer DNA binding in vitro. Expression of NPDC-1 was also observed to repress transcription mediated by retinoid receptors as well as by several other nuclear receptor family members, although not in a universal manner. CONCLUSIONS: These results suggest that NPDC-1, through direct interaction with retinoid receptors, functions to enhance the transcription complex formation and DNA binding function of retinoid receptors, but ultimately repress retinoid receptor-mediated gene expression. As with NPDC-1, retinoids and their receptors have been implicated in brain development and these data provide a point of convergence for NPDC-1 and retinoid mediation of neuronal differentiation.

Journal Article↗
PubMed1980

Retinoid metabolism and mode of action.

Vitamin A and its derivaties (retinoids) are necessary for the maintenance of normal phenotypic expression. An attempt at understanding the biochemical role of vitamin A had led to the demonstration of a new pathway for retinol. In this pathway, vitamin A is phosphorylated to retinylphosphate (RP), which is then glycosylated to retinylphosphatemannose (MRP). These two derivatives have been found in a variety of tissues in vivo and in vitro and appear to be ubiquitous components of cellular membranes. The suggestion has been made that MRP may mediate specific cellular interactions by functioning as a lipid intermediate in the biosynthesis of specific glycoconjugates. A study on spontaneously-transformed mouse fibroblasts (Balb/c 3T12-3 cells) has shown that retinoids are active in increasing the adhesive properties of these cells as measured in an EDTA-mediated detachment assay. Various retinoids were tested for their activity in the adhesion test, and this activity was found to correlate well with their biological activity in maintaining the expression of normal epithelial differentiation in other systems. Retinoic acid, 5,6-epoxyretinol, and 5,6-epoxyretinoic acid were the most active compounds. Retinoids without biological activity in other systems were also inactive in inducihg adhesive properties of 3T12-3 cells. Among these were the synthetic derivatives of retinol, anhydroretinol, and 4,5-monoeneperhydroretinol, and the phenyl derivative of retinoic acid. Beta-Ionone, abscisic acid, and juvenile hormone, which are devoid of vitamin A activity in other systems, were also inactive in this system. Retinoid-induced changes in cell surface proteins were investigated but no difference in 125I-fibronectin (MW 220,000) was detectable between retinoid-treated and untreated cells. However, these cells synthesized retinylphosphatemannose and the incorporation of 2-3H-mannose into a specific glycoprotein (gp 180) was found to be enhanced specifically by retinoid treatment. Investigations of the involvement of gp 180 in adhesion are in progress.

Animals↗
PubMed1996

Immunocytochemical localization of retinoid-binding protein in the dogfish retina.

PURPOSE: The cellular localization of retinoid-binding proteins has been extensively studied in the mammalian retina. Less is known about the distribution and identity of retinoid-binding proteins in lower vertebrate retinas. To understand their cellular functions, we have examined the distribution of specific retinoid-binding proteins in the neural retina and RPE of an elasmobranch, the dogfish. METHODS: Retinoid-binding proteins were localized in cryostat sections of dogfish eyes by the indirect immunofluorescence technique. We used well-characterized antibodies that have been previously employed for immunostaining. Immunoblotting was carried out to identify the antigen. RESULTS: The studies show that the cellular retinaldehyde-binding protein is present in the RPE and retinal Müller cells, and the interphotoreceptor retinoid-binding protein is found in the interstitial space between pigment epithelium and retina. CONCLUSIONS: The distribution of retinoid-binding proteins in dogfish retina is similar to that found in the mammalian retina which suggests that the sites of action of the retinoid-binding proteins are highly conserved in vertebrates.

Animals↗
PubMed2000

Differentiation-independent retinoid induction of folate receptor type beta, a potential tumor target in myeloid leukemia.

Folate receptor (FR) type beta is expressed in the myelomonocytic lineage, predominantly during neutrophil maturation and in myeloid leukemias. FR-beta expression was elevated up to 20-fold by all-trans retinoic acid (ATRA) in KG-1 myeloid leukemia cells in a dose-dependent and reversible manner in the absence of terminal differentiation or cell growth inhibition. ATRA also increased FR-beta expression in vitro in myeloid leukemia cells from patient marrow. FR-beta was not up-regulated in KG-1 cells treated with phorbol ester, dexamethasone, 1,25-dihydroxy vitamin D(3), or transforming growth factor beta. ATRA did not induce FR-beta expression in receptor negative cells of diverse origin. The ATRA-induced increase in FR-beta expression in KG-1 cells occurred at the level of messenger RNA synthesis, and in 293 cells containing a stably integrated FR-beta promoter-luciferase reporter construct, ATRA induced expression of the reporter. From experiments using retinoid agonists and antagonists and from cotransfection studies using the FR-beta promoter and expression plasmids for the nuclear receptors retinoic acid receptor (RAR)alpha, RARbeta, or RARgamma, it appears that the retinoid effect on FR-beta expression could be mediated by ligand binding to RARs alpha, beta, or gamma, but not to retinoid X receptors. Furthermore, there was apparent cross-talk between RARalpha and RARgamma selective agonists or antagonists, suggesting a common downstream target for RAR isoforms in inducing FR-beta expression. Thus, blocks in the RARalpha-specific pathway of retinoid-induced differentiation may be bypassed during retinoid induction of FR-beta expression. The results suggest that to facilitate FR-targeted therapies, retinoids may be used to modulate FR-beta expression in myeloid leukemia cells refractory to retinoid differentiation therapy.

Antineoplastic Agents↗
PubMed1991

Maintenance of opsin density in photoreceptor outer segments of retinoid-deprived rats.

Dietary deficiency in the retinoid precursors of the visual pigment chromophore 11-cis-retinal eventually results in selective degeneration of the photoreceptor cells of the vertebrate retina. Early effects of retinoid deficiency are depletion of rhodopsin from the retina and vesiculation of the photoreceptor outer segment disc membranes. Experiments were conducted to determine whether these early changes were accompanied by an alteration of the opsin content of the disc membranes. After being fed a retinoid-deficient diet containing retinoic acid for 26 weeks, the rhodopsin content of rat retinas was reduced by over 85%. Both the diameters and the lengths of the outer segments decreased significantly. However, immunocytochemical and freeze-fracture analyses indicated that retinoid deficiency did not lower opsin density in the outer-segment disc membranes. These findings indicate that in the rat, opsin synthesis and disc assembly are coordinated processes that remain coupled despite reduced availability of the vitamin A chromophore. The fact that disc size decreases and disc synthesis eventually ceases in retinoid-deprived rats indicates that specific retinoids are essential for disc morphogenesis. The mechanism by which these retinoids regulate disc assembly remains to be determined.

Analysis of Variance↗
PubMedDate not supplied

[Effect of retinoids on the growth of corneal endothelial cells in culture].

Corneal endothelium is a target tissue for retinoids and epidermal growth factor (EGF). We report here that retinoic acid and its synthetic analog, CBS-211 A (10(-8)-10(-7) M), enhance the mitogenic effect of EGF on cultured bovine corneal endothelial cells (BCEC). Furthermore, retinoid treatment increases the EGF-binding capacity of BCEC. The addition of cycloheximide (0.5 micrograms/ml) to cultures simultaneously with retinoids suppressed the retinoid effect on EGF-binding. These results suggest that retinoids could induce the expression of EGF receptors on BCEC as an early event. This study demonstrates a cooperation between retinoids and EGF in corneal endothelium and suggests that retinoids could have a beneficial effect on this tissue repair in vivo.

Animals↗
PubMed1985

Influence of retinoid nutritional status on cellular retinol- and cellular retinoic acid-binding protein concentrations in various rat tissues.

Studies were conducted to explore the effects of differences in retinoid nutritional status and of sex on the tissue distribution and levels of cellular retinol-binding protein (CRBP) and of cellular retinoic acid-binding protein (CRABP) in the rat. Sensitive and specific radioimmunoassays were developed and employed to measure the levels of both CRBP and CRABP. Four groups of six male rats each were fed experimental diets that differed greatly in the amount and kind of retinoids provided, but were otherwise identical. These groups were comprised of rats that were normal controls, retinoid-deficient, retinoic acid-fed, and excess retinol-fed. A fifth group of six female rats was fed the control diet. Immunogens identical with rat testis CRBP and CRABP, as assessed by radioimmunoassay displacement curves, were found in every rat tissue examined (21 tissues in males, 18 in females). The highest levels of CRBP were found in the proximal portion of the epididymis, the liver, and kidney. The highest levels of CRABP were found in the seminal vesicles, vas deferens, and skin. A significant (p less than 0.01) inverse relationship was found between CRBP and CRABP levels in the different tissues of the male reproductive tract. In both males and females, CRBP levels were highest in the gonads and proximal portion of the reproductive tract and decreased distally, whereas the opposite was true for CRABP. Retinoid-deficient rats showed reduced tissue levels of CRBP; thus, tissue CRBP levels are influenced by diet and retinoid availability. No differences in tissue CRBP levels were found in the rats fed the control, the retinoic acid, or the excess retinol diets. Female control rats had higher CRBP levels than male controls in 4 of 15 tissues compared (liver, lung, thymus, and fat). In contrast, tissue CRABP levels showed no diet- or sex-dependent differences. Only in one tissue, the skin, were differences observed (lower CRABP in retinoid-deficient and in female rats). Thus, CRABP metabolism and levels appear to be minimally influenced by the amount or kind of retinoid ligand available or by sex.

Animals↗
PubMed1983

Inhibition of carcinogenesis by retinoids.

Retinoids are effective inhibitors of chemical carcinogenesis in the mammary gland and urinary bladder of experimental animals. Modification of the basic retinoid structure has produced retinoids with increased target organ specificity, resulting in increased anticancer activity with reduced systemic toxicity. Combining retinoid treatment with hormonal manipulation results in a synergistic inhibition of mammary carcinogenesis; this combination approach also inhibits development of additional mammary cancers following surgical removal of the first mammary cancer. Retinoids are most effective when administered shortly after the carcinogenic insult. However, even when retinoid treatment is delayed, the compounds are still effective cancer chemopreventive agents for the mammary gland and urinary bladder. The length of time that retinoid exposure can be delayed and retain an anticancer effect is directly related to tumor latency, with a longer delay permissible against tumors with long latent periods.

Adenocarcinoma↗
PubMed1978

Assay of retinoids in biological samples by reverse-phase high-pressure liquid chromatography.

A separation procedure for retinoids based on reversephase high-pressure liquid chromatography with solvent mixtures of acetonitrile and water is described. The method may be applied to the screening of synthetic retinoids, which have potential for use in the prevention of cancer. It is easily adapted to a variety of biological samples and can be applied to other conventional retinoid assays in liver and plasma, detecting as little as 1 nmol retinyl esters and less than 0.3 nmol retinol per g tissue. The one-step chromatography results in separation and simultaneous determination of many of the synthetic retinoids and all of the natural retinoids, including the retinyl esters that are separated into their major fatty acid components. The method has been applied to the analysis of retinoid levels in the liver and intestine of vitamin A-deficient hamsters following a p.o. dose (0.5 mg/day for 2 days) of retinyl acetate or of a synthetic vitamin A analog and is predictive of the degree to which various synthetic retinoids can be converted to retinol and stored in the liver as retinyl esters. Because of its speed, excellent recoveries, and high resolution, the method offers significant advantages over previous, more lengthy procedures.

Animals↗
PubMed1981

Retinoid effects on epidermal structure, differentiation, and permeability.

Retinoids profoundly influence epidermal differentiation, but neither the nature of their antikeratinizing activity nor their mechanism of action is known. In this study, we have correlated morphologic and histochemical findings with an assessment of stratum cohesion and water barrier integrity in adult hairless mice treated with either 13-cis-retinoic acid or the aromatic retinoid, RO 10-9359. Both the synthetic retinoids produced dose-dependent alterations in transepidermal water loss, which were about 5 to 10 times greater in RO 10-9359-treated animals. In contrast to essential fatty acid deficiency, where diminished intercellular lamellar lipids may account for defective barrier function, these lipid-rich structures were intact in retinoid-treated tissues. Instead, retinoids produced both epidermal and stratum corneum loosening, manifested both by the ready production of intraepidermal friction blisters and by ease of removal of cornified cells by tape stripping. Dyshesion correlated with loss of desmosomes and intra- and intercellular accumulation of amorphous material in the upper epidermis. Since these deposits lacked the tinctorial properties of mucin, dyshesion could not be ascribed to the development of mucous metaplasia. Finally, dyshesion could not be attributed to either gain or loss of membrane sugars demonstrated with rhodamine-conjugated lectins, since these changed only late in the course of retinoid treatment. We conclude that the antikeratinizing basis for retinoid activity comprises: (1) dose-dependent alterations in transepidermal water loss and (2) epidermal and stratum corneum loosening, which may, in turn, lead to loss of epidermal cohesion and abnormal barrier function. Neither mucous metaplasia nor stratum corneum thinning appear to play a major role.

Animals↗
PubMed1980

Inhibition of carcinogenesis by retinoids.

Experimental investigations of the antineoplastic effects of retinoids are reviewed in this paper. In vitro studies have shown that the hyperplastic and metaplastic response to chemical carcinogens of mouse prostate cultures is suppressed by the addition of retinoids to the culture medium, that retinoids can partially inhibit the morphologic transformation of 10T 1/2 cells by physical or chemical carcinogens, and that the growth of some non-neoplastic and some neoplastic cell lines can be inhibited by retinoids. In vivo studies have shown that retinoids can suppress papilloma and carcinoma development (the promotion phase) in the two-stage skin carcinogenesis assay, inhibit mammary and bladder carcinogenesis in mice and rats, and inhibit the growth of some transplantabletumor lines. So far it has not been possible to inhibit predictably tumour formation in the intestinal tract or the respiratory tract of rodents. Almost all the synthetic retinoids have a higher therapeutic index than the natural retinoids in the prevention or treatment of cancer.

Animals↗
PubMed1980

Relationships among retinoid structure, inhibition of growth, and cellular retinoic acid-binding protein in cultured S91 melanoma cells.

S91 melanoma cells, which are sensitive to retinoic acid and contain a cellular retinoic acid-binding protein (RABP), were used in an investigation of the possible correlation between the capacities of various retinoids to inhibit cell proliferation and to bind to the RABP. Each of 27 different retinoids was evaluated for growth-inhibitory activity by exposing S91 melanoma cells to various retinoid concentrations between 1 nM and 10 microM. Subsequently, the ability of 17 of these retinoids to compete with [3H]retinoic acid for binding to RABP was determined. The results demonstrate that in addition to retinoic acid, many retinoids are capable of inhibiting the proliferation of S91 melanoma cells, although some are considerably less active. A positive correlation was found between the abilities of retinoids possessing a free carboxyl group at carbon 15 to inhibit cell proliferation and to bind to RABP. The structure-activity relationships established with the S91 cells are compared with previous reports on the biological activities of various retinoids in other systems.

Animals↗
PubMed1980

Inhibition by an aromatic retinoid of DNA damage induced by the bladder carcinogen N-butyl-N-(3-carboxypropyl)nitrosamine.

The reversible inhibitory action of an aromatic analog of retinoic acid, ethyl all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoate (aromatic retinoid) on bladder carcinogenesis was studied by biochemical and histopathological methods. fischer 344 female rats were fed a diet containing the aromatic retinoid (0, 12.5 or 50 ppm) for 56 days. On day 57, 60 or 70, 50 mg/kg body weight of N-butyl-N-(3-carboxypropyl)nitrosamine (BCPN) in a volume of 0.3 ml was directly instilled intravesically through a urethral catheter. DNA damage in rat bladder epithelial cells 2, 24 and 48 hr after administration of BCPN was examined by measuring the change in sedimentation profile of the DNA in 5 approximately 20% alkaline sucrose gradients. DNA sedimentation was measured by a fluorometric procedure. Histopathological examination of the bladder epithelium was performed at the same time. Two hours after a 5-min exposure to BCPN, DNA damage at the urothelium was observed in rats fed the diet without the aromatic retinoid, but the damage was repaired after 24 and 48 hr. The highest dose of the aromatic retinoid almost completey prevented DNA damage by BCPN on days 57 and 60. A lower dose of the aromatic retinoid did not prevent DNA damage by BCPN on days 57, 60, and 70, while the higher dose did not prevent damage by BCPN on day 70. No histological changes were observed in the urothelium of rats treated with the aromatic retinoid and BCPN, and electron microscopy showed that the epithelium also remained normal. DNA damage was induced by BCPN at the urothelium, and the damage was inhibited by previous administration of the aromatic retinoid.

Animals↗
PubMed2002

Nicotine modulates the effects of retinoids on growth inhibition and RAR beta expression in lung cancer cells.

Epidemiological and animal studies have demonstrated that vitamin A and its natural and synthetic derivatives, retinoids, are effective agents in preventing the development of tobacco-associated cancers. Unfortunately, clinical trials of retinoids on cigarette smokers have shown lack of efficacy in preventing lung cancer. In our study, we investigated the effect of nicotine on the anti-cancer activity of all trans-retinoic acid (trans-RA) in human lung cancer cells. Our results demonstrated that nicotine could abrogate the growth inhibitory effect of trans-RA by suppressing its ability to induce the expression of RA receptor beta (RAR beta), a tumor suppressor. The inhibitory effect of nicotine was accompanied with induction of orphan receptor TR3. Inhibition of TR3 expression by overexpression of TR3 anti-sense RNA in H460 lung cancer cells strongly prevented the suppressive effect of nicotine on trans-RA activity. Treatment with nicotine or the cotransfection of TR3 expression vector inhibited the induction of RAR beta promoter activity by trans-RA in transient transfection assays. The inhibition of RAR beta promoter activity was due to the interaction of TR3 with orphan receptor COUP-TF, resulting in inhibition of COUP-TF DNA binding and transactivation on the RAR beta promoter. Furthermore, we found that nicotine failed to suppress the effect of a retinoid X receptor (RXR)-selective retinoid SR11237 on inducing both growth inhibition and RAR beta promoter activity, due to the ability of SR11237 to activate the RAR beta promoter through the RXR/TR3 heterodimer. Together, our results demonstrate that nicotine suppresses the growth inhibitory effects of trans-RA by inhibiting RAR beta expression through its induction of TR3 expression and suggest that RXR-selective retinoids may be more effective than classical retinoids for preventing and treating tobacco-associated cancers.

Benzoates↗
PubMed1994

Retinoids are positive effectors of adipose cell differentiation.

Retinoids, especially all-trans retinoic acid (t-RA), have been reported in the last decade to inhibit the differentiation of preadipose cells. In those studies, however, the concentrations of t-RA were supraphysiological (0.1-10 microM range). In contrast we show that, when present at concentrations below or close to the Kd values of retinoic acid receptors, retinoids behave as potent adipogenic hormones (1 pM to 10 nM range). As shown by the use of specific ligands for each RAR subtype, these positive effects on adipose differentiation involve in particular the RAR alpha subtype, and have been observed in Ob17 cells exposed to serum-supplemented or serum-free medium, and in rat preadipocytes exposed to serum-free medium. Among the two classes of retinoid acid receptors (RARs) and retinoid X receptors (RXRs), RAR alpha, RAR gamma, RXR alpha and RXR beta mRNAs could be detected in growing adipoblasts and were found to be increased in committed preadipocytes and differentiated cells upon retinoid treatment. Like other adipogenic hormones, retinoids were only effective in the terminal differentiation process leading from preadipocytes to adipocytes.

Adipocytes↗
PubMed2002

Retinoid regulation of the phosphoenolpyruvate carboxykinase gene in liver.

The cytosolic PEPCK gene is a model gene for assessing retinoid regulation of liver-specific genes encoding enzymes of carbohydrate metabolism. In vivo, we have demonstrated that the PEPCK gene is inhibited by vitamin A deficiency. Specifically, under conditions of food deprivation, induction of the PEPCK gene is inhibited in the vitamin A deficient mouse. Inhibition of the PEPCK gene by vitamin A deficiency is reversed by all-trans or 9-cis retinoic acid (RA) treatment. In a transgenic mouse model, a -460 and -355 bp PEPCK promoter fragment confers susceptibility to inhibition by vitamin A deficiency and responsiveness to all-trans RA treatment. However, there is a differential effect of 9-cis RA on the PEPCK promoter; the -460 fragment confers responsiveness to 9-cis RA, but the -355 fragment does not. Taken together, these results indicate that the PEPCK retinoic acid response element (RARE)1 is required for 9-cis RA induction-but not all-trans RA induction-of the PEPCK gene. In order to determine if vitamin A deficiency alters specific localized expression of the PEPCK gene in the periportal cells of the liver, the effect of vitamin A status on PEPCK localization in the liver was also measured. The PEPCK transgenes were expressed specifically in the periportal region of the liver acinus and although vitamin A deficiency caused a decrease in PEPCK transgene mRNA levels in periportal cells, it did not alter the periportal cell-specific pattern of expression. Retinoid treatment induced PEPCK transgene mRNA levels in the same population of cells, however, the -355 bp PEPCK promoter fragment did not respond to 9-cis RA treatment. In order to determine the nuclear transcription factor(s) responsible for retinoid regulation of the PEPCK gene in the liver, we investigated retinoic acid receptor (RAR)alpha and beta and the retinoid X receptor (RXR)alpha-the major retinoid receptors in liver-in terms of expression and the ability of the receptors to bind the PEPCK RAREs. Vitamin A deficiency significantly decreased hepatic RAR beta, but not RAR alpha or RXR alpha mRNA levels. In situ hybridization showed that RAR alpha, RAR beta and RXR alpha mRNAs were localized in the periportal region, however, immunohistochemistry showed that RAR alpha and RXR alpha were distributed evenly across the liver acinus, whereas only RAR beta levels were higher in periportal cells. The binding of nuclear receptors to PEPCK RARE1, RARE2 and RARE3 indicates a complex pattern of retinoid receptor and orphan nuclear receptor binding.

Animals↗
PubMed1994

A new class of retinoids with selective inhibition of AP-1 inhibits proliferation.

Retinoids regulate many biological processes, including differentiation, morphogenesis and cell proliferation. They are also important therapeutic agents, but their clinical usefulness is limited because of side effects. Retinoid activities are mediated by specific nuclear receptors, the RARs and RXRs, which can induce transcriptional activation through specific DNA sites or by inhibiting the transcription factor AP-1 (refs 12-15), which usually mediates cell proliferation signals. Because the two types of receptor actions are mechanistically distinct, we investigated whether conformationally restricted retinoids, selective for each type of receptor action, could be identified. Here we describe a new class of retinoids that selectively inhibits AP-1 activity but does not activate transcription. These retinoids do not induce differentiation in F9 cells but inhibit effectively the proliferation of several tumour cell lines, and could thus serve as candidates for new retinoid therapeutic agents with reduced side effects.

Animals↗