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PubMed1996

AGN193109 is a highly effective antagonist of retinoid action in human ectocervical epithelial cells.

Retinoids are important physiological agents that regulate epithelial cell differentiation and proliferation. The importance of these agents in regulating growth, development, and differentiation has led to a search for new retinoid agonists and antagonists. In the present manuscript we show that AGN193109, a retinoid analog, is an efficient antagonist of retinoid action in human cervical epithelial cells. Treatment of ECE16-1 cells with natural or synthetic retinoids reduces cytokeratin K5, K6, K14, K16, and K17 levels, increases cytokeratin K7, K8, and K19 levels, increases retinoic acid receptor-beta (RAR beta) mRNA levels, suppresses proliferation, and alters cell morphology. Co-treatment with AGN193109 prevents these responses. Half-maximal and maximal antagonism is observed at a molar ratio of AGN193109: retinoid agonist of 1:1 and 10:1, respectively. When administered alone AGN193109 has no agonist activity. Thus, AGN193109, which binds to RAR alpha, RAR beta, and RAR gamma with Kd values = 2,2, and 3 nm, respectively, but is unable to bind to the retinoid X receptors, is a highly active antagonist of retinoid action in ECE16-1 cells.

Cell Division↗

PubMed2001

Vitamin A: recent advances in the biotransformation, transport, and metabolism of retinoids.

Advances in vitamin A research in 1999 and 2000 have improved the understanding the molecular processes through which beta-carotene and other provitamin A carotenoids are converted to vitamin A, the roles of cellular retinoid-binding proteins that serve as retinoid chaperones during metabolism, the regulation of retinoid transport, and the nature and regulation of several enzymes required for the absorption, storage, activation, and inactivation or degradation of retinoids. Not only has a clearer picture emerged of specific molecular processes, but it is also becoming evident that whole-body retinoid homeostasis is facilitated by close communication among organs due to the rapid interorgan recirculation of retinoids, and by the "autoregulation" by retinoic acid of several enzymes and retinoid-binding proteins that mediate retinoid homeostasis.

Journal Article↗

PubMed2005

Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. Updated analysis of the long-term follow-up data.

Oral administration with acyclic retinoid, a synthetic vitamin A analog, for a limited period of 12 months (48 weeks) prevented the development of second primary hepatocellular carcinoma (HCC) and also improved the survival of patients who underwent curative treatments of the initial tumor. Following that randomized controlled study reported in 1996 and 1999, we have continued to follow up the patients by medical imaging and blood chemical analyses, and found that the preventive effect of acyclic retinoid lasted up to 199 weeks after randomization (or 151 weeks after completion of retinoid administration). The retinoid's effect was not mediated by reduction in hepatic necro-inflammation since no significant decrease in serum aminotransferase activity was seen in the retinoid group. Such observation seems quite distinct from the cancer-preventive mechanism of interferon, a potent immunopreventive agent for HCC. We have also shown here the reduction by the retinoid in serum levels of lectin-reactive alpha-fetoprotein (AFP-L3) and protein induced by vitamin K absence or antagonist-II (PIVKA-II), both of which indicate the presence of latent HCC cells. These results suggest that acyclic retinoid may delete such malignant clones before they expand to clinically detectable tumors and thereby inhibited second primary HCC. Once such latent clones are eradicated, it may well take at least several years for the next cancer clone to arise clinically. This may possibly explain a reason for the long-term effect of the retinoid even after the limited period of administration.

Antineoplastic Agents↗

PubMed1999

Role of retinoid receptors in the regulation of mucin gene expression by retinoic acid in human tracheobronchial epithelial cells.

To investigate which retinoid receptors are critical in the regulation by all-trans-retinoic acid (RA) of the mucin genes MUC2, MUC5AC and MUC5B in cultured normal human tracheobronchial epithelial (NHTBE) cells, we used pan-RAR-, pan-RXR- and RAR- isotype (alpha, beta and gamma)-selective agonists and RARalpha- and RARgamma-selective antagonists (RAR is RA receptor and RXR is retinoid X receptor). RAR-, RARalpha- and RARgamma-selective agonists strongly induced mucin mRNAs in a dose-dependent manner, while the RARbeta-selective retinoid only weakly induced mucin gene expression at very high concentrations (1 microM). The pan-RXR-selective agonist by itself did not induce mucin gene expression, but acted synergistically with suboptimal concentrations of the pan-RAR agonist. A retinoid with selective anti-activator-protein-1 activity only marginally induced mucin gene expression. The RARalpha antagonist strongly inhibited mucin gene induction and mucous cell differentiation caused by RA and by the RARalpha- and RARgamma-selective retinoids. In contrast, the RARgamma antagonist only weakly inhibited RARalpha-selective-retinoid-induced mucin gene expression, but completely blocked mucin gene expression induced by the RARgamma-selective retinoid. Our studies indicate that RARalpha is the major retinoid receptor subtype mediating RA-dependent mucin gene expression and mucous cell differentiation, but that the RARgamma isotype can also induce mucin genes. Furthermore these studies suggest that RARbeta is probably not (directly) involved in RA-induced mucin gene expression.

Base Sequence↗

PubMed1986

Quantitative analysis of the effect of retinoids on facial morphogenesis.

Retinoids have been applied to stage 20 chick embryos by using beads that act as controlled release carriers. With beads soaked in high concentrations of all-trans-retinoic acid, the face, in addition to the wing, is affected. Severe bilateral clefting of the primary palate results; the upper beak is completely missing, whereas the lower beak is unaffected. By using a scoring system that quantitates the severity of the upper beak defect, dose-response curves have been obtained. With beads soaked in progressively higher concentrations of retinoic acid, the upper beaks are increasingly truncated. The synthetic retinoid TTNPB also causes beak defects and is 30 times more potent than all-trans-retinoic acid. By removing beads soaked in retinoids at different times after implantation, the effect of varying the length of exposure of the developing face to retinoids has been examined. The production of beak defects is a two-step process and only a short exposure to retinoid is required to produce clefting. There are striking similarities in the dose-time relationships of retinoid treatments that are required to bring about beak defects and pattern changes in the limb. The outgrowth and development of spatially defined patterns of connective tissue within the upper beak appear analogous to processes involved in limb morphogenesis. We propose that retinoids may act by the same mechanisms in both systems. An unsolved puzzle is why retinoids specifically affect the development of the upper beak.

Animals↗

PubMed1983

Divergent effects of retinoids on pancreatic and liver carcinogenesis in azaserine-treated rats.

Chemoprevention by synthetic retinoids of the progression of carcinomas of the pancreas induced in rats by azaserine was evaluated. Lewis rats were given five weekly injections of azaserine, 30 mg/kg, while being fed a chow diet. Two weeks after completion of carcinogen treatment, groups of rats were fed the chow diet supplemented with four different retinoids at the level of 0.5 to 2 mmol/kg of diet for 1 year. The incidence of pancreatic and other neoplasms was determined by autopsy and histological study. The incidence of localized pancreatic carcinoma among male and female non-retinoid-treated controls was 25 and 17%, respectively. No invasive or metastatic carcinomas were found in the control group. The combined incidence of localized and invasive pancreatic carcinomas among male and female rats treated with retinoids was: N-(4-pivaloyloxyphenyl)retinamide, 4 and 0%; N-(2-hydroxypropyl)retinamide, 14 and 6%; N-(3-hydroxypropyl)retinamide, 16 and 4%; and N-(2,3-dihydroxypropyl)retinamide, 12 and 6%. High- and low-dose groups are combined in this summary of data. Thus, there was a trend towards fewer pancreatic carcinomas among all retinoid-treated groups. The reduction in incidence was significant in both male and female rat groups given N-(4-pivaloyloxyphenyl)retinamide and N-(2,3-dihydroxypropyl)retinamide. The principal evidence of retinoid toxicity was growth failure, which was most severe in animals treated with N-(4-pivaloyloxyphenyl)retinamide, and testicular atrophy, which was most severe among male animals treated with N-(3-hydroxypropyl)retinamide. Among the females, groups treated with three of the four retinoids showed a dose-related increase in incidence of hepatocellular carcinomas. Since the retinoids were fed after the completion of exposure to the carcinogen, the effects on both pancreatic and liver carcinogenesis were exerted during the postinitiation phase of carcinogenesis.

Animals↗

PubMed1976

Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids).

An approach to chemoprevention of common forms of epithelial cancer, during the period of preneoplasia, is described. Vitamin A and its synthetic analogs (retinoids) are potent agents for control of cell differentiation in many epithelial tissues. Direct effects of retinoids on normal and preneoplastic cell differentiation can be measured in organ culture. In experimental animals, deficiency of dietary retinoids enhances susceptibility to chemical carcinogenesis. Natural retinoids, fed at high dietary levels, have some ability to prevent chemical carcinogenesis in epithelial tissues of bronchi, trachea, stomach, uterus, and skin of experimental animals. However, natural retinoids have limited usefulness for chemoprevention of cancer because of inadequate tissue distribution and excessive toxicity. Synthetic retinoids have been made and shown to be more potent and less toxic for prevention of cancer in animals. Several structural modifications of the ring and terminal portions of the retinoid molecule have significant biological activity; modification of the side chain has been more difficult. The potential future usefulness of this approach to cancer prevention in man will depend on further synthetic modification of the retinoid molecule.

Animals↗

PubMed1993

Retinoids increase urokinase-type plasminogen activator production by human retinal pigment epithelial cells in culture.

PURPOSE: To examine the effect of two retinoids, all-trans-retinoic acid (tretinoin) and all-trans-9-(4-methoxy-2,3,6- trimethylphenyl)-3,7-dimethyl- 2,4,6,8-nonatetraenoic acid (acitretin) on the production of plasminogen activators and plasminogen activator inhibitors by human retinal pigment epithelial cells in culture. METHODS: Cultures of human retinal pigment epithelial cells were incubated with either of the retinoids at a concentration of 1 microM for 24-72 hours. The media were assayed using solid-phase immunocapture assays and zymography. RESULTS: Both retinoids caused a twofold to sevenfold increase in urokinase-type plasminogen activator in the medium. The effect was seen after 24 hours in culture and was further augmented up to 72 hours. No significant amounts of tissue-type plasminogen activator were detected. The plasminogen activator inhibitor activity was unaffected by the retinoids. Proliferation and morphology of retinal pigment epithelial cells were also unaffected by the retinoids in incubations for up to 72 hours. CONCLUSIONS: Retinoids profoundly affect the extracellular proteolysis of retinal pigment epithelial cells in culture. This effect may be related to the differentiation-inducing activity of retinoids seen in other cell types, often connected with changes in extracellular proteolysis. It is possible that retinoids may modulate dedifferentiation, proliferation, and migration of retinal pigment epithelial cells seen in vitro, as well as in the pathogenesis of retinal disease.

Acitretin↗

PubMed1998

Effects of conformationally restricted synthetic retinoids on ovarian tumor cell growth.

We have used conformationally restricted retinoids to investigate the role of individual RAR subtypes and RXR in mediating the growth response of ovarian tumor cells to retinoids. Our results show that treatment of all-trans-RA-sensitive CAOV-3 cells with retinoids that bind and activate a single RAR or RXR led to a partial inhibition of growth. Treatment of all-trans-RA- resistant SKOV-3 cells did not alter growth. Maximum inhibition of growth, comparable to that observed following treatment with natural retinoids such as all-trans-RA and 9-cis-RA, was obtained only following treatment with a combination of an RAR-selective compound and an RXR-selective one. These results suggest that activation of both RAR and RXR classes is required in order to obtain maximum inhibition of ovarian tumor cell growth by retinoids. In addition, one compound, AHPN, was found to inhibit both RA-sensitive CAOV-3 and RA-resistant SKOV-3 cells. Further study of the effects of this retinoid showed that AHPN acts through an apoptotic pathway. Taken together, our results suggest that retinoids may serve as effective anti-proliferative agents in the treatment of ovarian cancer.

Apoptosis↗

PubMed1996

Role of thyroid hormone and retinoid receptors in the homeotic transformation of tails into limbs in frogs.

We provide here further data on the dramatic homeotic transformation of tails into limbs which is induced by retinoids during frog tadpole tail regeneration. The effect can still be produced up to nine days after tail amputation by which time tail regeneration has essentially been completed. Complete tail amputation is needed for the effects to be manifest, partial damage of various sorts to the tail is not enough. We show that as well as retinyl palmitate, other retinoids such as all-trans-retinoic acid and TTNPB, which is a RAR specific retinoid, can induce the homeotic transformation. TTNPB has a 300 x greater potency than retinoic acid. Prolactin, which inhibits thyroid hormone production, prevents the appearance of limbs on the tail from which we conclude that thyroid hormone is needed. We present preliminary evidence from RT-PCR that all six retinoid receptors, the three retinoic acid receptors (RARs), and the three retinoid X receptors (RXRs), are present in the normal tail blastema and that after retinoid treatment RAR alpha, RXR alpha, and RXR beta may be up-regulated. Finally, we show that when RA synthesis is inhibited, normal tail regeneration is inhibited. We conclude that tail regeneration depends upon a particular endogenous level of RA, but that when this level is raised by external administration and thyroid hormone receptors are present the up-regulation of certain retinoid receptors allows novel nuclear receptor interactions which results in the induction of limb-specific genes leading to the appearance of limbs on the tail.

Amputation, Surgical↗

PubMed1997

Biological assay for activity and molecular mechanism of retinoids in cervical tumor cells.

The composition and response of the retinoid signaling pathway in a human cell line (CC-1), representative of a low grade cervical carcinoma, were evaluated. Reverse-transcriptase polymerase chain reaction (RT-PCR) analysis demonstrated expression of cytoplasmic retinol binding protein, CRBPI, cytoplasmic retinoic acid binding protein, CRABPII, and nuclear retinoic acid receptors, RAR alpha, RARgamma, RXR alpha, and RXRbeta, but not CRABPI or RARbeta. This pattern is similar to that of the ectocervix. Activation of endogenous nuclear receptors was evaluated in a reporter subline of CC-1, called CC-B, containing a reporter gene controlled by a retinoic acid responsive element (RARE) and thymidine kinase promoter. Retinoid treatment of CC-B resulted in dose-dependent increases in reporter gene expression. Retinoids inhibited growth at concentrations greater than 100 nM. 9-cis retinoic acid (1 nM) significantly stimulated growth. Immunohistochemical analysis of CC-B organotypic cultures demonstrated a high level of epidermal growth factor receptor (EGF-R) expression that was decreased by retinoids. The degree of RARE transactivation induced by retinoids significantly correlated with the degree of inhibition of growth (R = -0.96) and EGF-R expression (R = -0.92). The dose-dependent and retinoid-specific responses of CC-1 at the molecular and biological levels demonstrate the utility of this reporter cell line for evaluation of retinoid activities.

Cell Division↗

PubMed2026

Retinoid dynamics in immune cells during age-related diseases.

Retinoids comprise vitamin A and its structurally related natural and synthetic derivatives. Retinoid dynamics involves multiple retinoid forms, carrier proteins, and enzymes that orchestrate the absorption, transport, storage and biotransformation of dietary vitamin A. Beyond their canonical metabolic functions, metabolites and proteins involved in retinoid metabolism also play distinct roles in signal transduction and transcriptome reprogramming, broadening the mechanisms that influence immune cell fate decisions. Age‑related changes in retinoid bioavailability and signaling intensity alter immune cell polarization and function, thereby contributing to the pathogenesis of chronic inflammation in neurodegenerative diseases, cardiovascular diseases, osteoarthritis, and other age-related diseases. In this review, we focus on age-related alterations in the retinoid metabolic pathway and their impact on inflammation and the progression of age-related diseases. This review highlights the pivotal role of retinoid metabolism in anti-ageing interventions and considers future directions and challenges in this field.

Humans↗

PubMed2006

Therapeutic advances in cutaneous T-cell lymphoma (CTCL): from retinoids to rexinoids.

Retinoids comprise a family of polyisoprenoid lipids that include vitamin A (retinol) and its various natural and synthetic analogues. Retinoids are compounds with multiple actions. They are involved in the control of cell proliferation, cell differentiation, and embryonic development. Each retinoid has its own profile of pharmacologic properties that determines its usefulness in clinical dermatology or oncology. Although numerous synthetic retinoids have been synthesized, their biological activities are usually associated with clinical disadvantages such as toxicity and teratogenicity. Retinoids that bind to both the retinoic acid receptor and retinoid X receptor subtypes have shown clinical activity in hematologic malignancies and can mediate genes associated with both growth and differentiation. Retinoid X receptor-specific rexinoids have also shown efficacy in the treatment of cutaneous T-cell lymphomas, but their exact mechanism of action is unclear. This article summarizes the clinical relevance of both groups of compounds in this important patient population.

Humans↗

PubMed1998

Anticoagulant effects of synthetic retinoids and activated vitamin D3.

We have recently found that retinoic acids (RAs) evoke an anticoagulant effect by upregulating thrombomodulin (TM) and downregulating expression of tissue factor (TF) in acute promyelocytic leukemia (APL) and monoblastic leukemia cells. Two classes of nuclear RA receptors, termed retinoic acid receptors (RARs) and retinoid X receptors, have already been identified. Each receptor class consists of three subtypes. We have used several synthetic retinoids to find which receptor subtypes are involved in the regulation of TM and TF expression in APL cells NB4, monoblastic leukemia cells U937, and human umbilical vein endothelial cells (HUVECs). Am80, which does not have a binding affinity to RARgamma; Ch55, which does not bind to cytoplasmic retinoic acid-binding protein (CRABP); and a specific RARalpha agonist, Ro40-6055, have been shown to upregulate TM and downregulate TF in NB4 and U937 cells similar to all-trans RA (ATRA). A specific RARalpha antagonist, Ro41-5253, efficiently suppressed the upregulation of TM by ATRA and Am80 in NB4 cells, U937 cells and HUVECs. In contrast, only when both RARalpha and RARbeta antagonists were preincubated, downregulation of TF by the retinoids was suppressed in NB4 cells. Furthermore, 1,25(OH)2D3 has been shown to have anticoagulant effects on several monocytic leukemia cells and monocytes similar to RAs. These results indicate the mechanically distinct transactivation and transrepression functions of RARs, the major role of RARalpha in TM upregulation by retinoids in leukemic cells and HUVECs, and the cooperative role of RARalpha and RARbeta in TF downregulation by retinoids. It is also implied that synthetic retinoids and vitamin D derivatives will provide very useful means to control distinct targets--TM and TF genes--at the level of transcription. Synthetic retinoids and vitamin D derivatives may develop as new types of antithrombotic and antiatherosclerotic agents which change the character of cells as well as malignant cell differentiation inducers.

Anticoagulants↗

PubMed1995

Evidence for the involvement of retinoic acid receptor RAR alpha-dependent signaling pathway in the induction of tissue transglutaminase and apoptosis by retinoids.

In this study, we show that all-trans-retinoic acid (RA) is a potent inducer of tissue transglutaminase (TGase II) and apoptosis in the rat tracheobronchial epithelial cell line SPOC-1. We demonstrate that these cells express the retinoid receptors RAR alpha, RAR gamma, and RXR beta. To identify which of these receptors are involved in regulating these processes, we analyzed the effects of several receptor-selective agonists, an antagonist, and a dominant-negative RAR alpha. We show that the RAR-selective retinoid SRI-6751-84 strongly increased TGase II expression at both the protein and mRNA levels, whereas the RXR-selective retinoid SR11217 had little effect. The RAR alpha-selective retinoid Ro40-6055 was also able to induce TGase II, whereas the RAR gamma-selective retinoid CD437 was inactive. The induction of TGase II by the RAR-selective retinoid was completely inhibited by the RAR alpha-antagonist Ro41-5253. Overexpression of a truncated RAR alpha gene with dominant-negative activity also inhibited the induction of TGase II expression. The increase in TGase II is associated with an induction of apoptosis as revealed by DNA fragmentation and the generation of apoptotic cells. We demonstrate that apoptosis is affected by retinoids in a manner similar to TGase II. Our results suggest that the induction of TGase II expression and apoptosis in SPOC-1 cells are mediated through an RAR alpha-dependent signaling pathway.

Animals↗

PubMed1999

Identification of a novel class of retinoic acid receptor beta-selective retinoid antagonists and their inhibitory effects on AP-1 activity and retinoic acid-induced apoptosis in human breast cancer cells.

Four candidate retinoid antagonists (LE135, LE511, LE540, and LE550) were designed on the basis of the ligand superfamily concept and synthesized. Analysis of these related retinoids by transient transfection assay demonstrated that LE135, LE540, and LE550 are effective retinoic acid receptor (RAR) antagonists, whereas LE511 selectively induced RARbeta transcriptional activity. Both LE135 and LE540 inhibited retinoic acid (RA)-induced transcriptional activation of RARbeta, but not RARalpha, RARgamma or retinoid X receptor alpha (RXRalpha), on a variety of RA response elements. The retinoid antagonists also inhibited all-trans-RA-induced transcriptional activation of RARbeta/RXRalpha heterodimers, although they did not show any effect on transactivation activity of RXR/RXR homodimers. In ZR-75-1 human breast cancer cells, cotreatment of LE135 and LE540 with all-trans-RA inhibited all-trans-RA-induced apoptosis of the cells, further demonstrating that RARbeta plays a role in RA-induced apoptosis of breast cancer cells. We also evaluated the effect of these retinoids on AP-1 activity. Our data showed that LE135 and LE540 strongly repressed 12-O-tetradecanoylphorbol-13-acetate-induced AP-1 activity in the presence of RARbeta and RXRalpha. Interestingly, LE550 induced AP-1 activity when RARbeta and RXRalpha were expressed in HeLa cells but not in breast cancer cells. These results demonstrate that LE135 and LE540 were a novel class of RARbeta-selective antagonists and anti-AP-1 retinoids and should be useful tools for studying the role of retinoids and their receptors.

Animals↗

PubMed2001

Retinoids inhibit the actions of angiotensin II on vascular smooth muscle cells.

Retinoids are derivatives of vitamin A and powerful inhibitors of cell proliferation and inflammation. Angiotensin II (Ang II) contributes to vascular lesions by promoting cell growth of vascular smooth muscle cells (VSMCs). Therefore, we examined whether retinoids interfere with the proproliferative actions of Ang II in VSMCs via AT(1) receptor-dependent or activator protein-1 (AP-1)-dependent mechanisms. VSMCs express retinoid receptor proteins, ie, retinoic acid receptor (RAR) alpha and retinoid X receptor (RXR) alpha. Long-term exposure to 1 micromol/L all-trans retinoic acid (RA) dose-dependently inhibited Ang II-induced cell proliferation (P<0.005) as well as DNA and protein synthesis (P<0.001). All-trans RA blocked Ang II stimulation of transforming growth factor-beta(1) mRNA (P<0.005). All-trans RA inhibition of vascular VSMC growth was mediated both via RAR- and RXR-dependent pathways, as shown by receptor-specific synthetic retinoids. Transfection experiments revealed that inhibition of AP-1-dependent gene transcription is one mechanism by which all-trans RA inhibits Ang II action. RARalpha cotransfection enhanced the anti-AP-1 effects of all-trans RA dose-dependently. AP-1 activity was similarly inhibited by cotransfection with either RARalpha or RXRalpha. Ang II-induced gene expression of c-fos was abrogated by all-trans RA treatment (P<0.005). In VSMCs, all-trans RA downregulated AT(1) receptor mRNA (P<0.01) and reduced B(max) (P<0.001). All-trans RA repressed Ang II-stimulated AT(1) receptor promoter activity. The all-trans RA inhibitory effect was abolished when the AP-1 consensus site on the AT(1) receptor promoter was deleted. Our findings demonstrate that retinoids are potent inhibitors of the actions of Ang II on VSMCs. The findings support the notion that retinoids may interfere with proliferative vascular disease.

Alitretinoin↗

PubMed2003

Bovine cumulus-granulosa cells contain biologically active retinoid receptors that can respond to retinoic acid.

Retinoids, a class of compounds that include retinol and its metabolite, retinoic acid, are absolutely essential for ovarian steroid production, oocyte maturation, and early embryogenesis. Previous studies have detected high concentrations of retinol in bovine large follicles. Further, administration of retinol in vivo and supplementation of retinoic acid during in vitro maturation results in enhanced embryonic development. In the present study, we hypothesized that retinoids administered either in vivo previously or in vitro can exert receptor-mediated effects in cumulus-granulosa cells. Total RNA extracted from in vitro cultured cumulus-granulosa cells was subjected to reverse transcription polymerase chain reaction (RT-PCR) and mRNA expression for retinol binding protein (RBP), retinoic acid receptor alpha (RARalpha), retinoic acid receptor beta (RARbeta), retinoic acid receptor gamma (RARgamma), retinoid X receptor alpha (RXRalpha), retinoid X receptor beta (RXRbeta), retinaldehyde dehydrogenase-2 (RALDH-2), and peroxisome proliferator activated receptor gamma (PPARgamma). Transcripts were detected for RBP, RARalpha, RARgamma, RXRalpha, RXRbeta, RALDH-2, and PPARgamma. Expression of RARbeta was not detected in cumulus-granulosa cells. Using western blotting, immunoreactive RARalpha, and RXRbeta protein was also detected in bovine cumulus-granulosa cells. The biological activity of these endogenous retinoid receptors was tested using a transient reporter assay using the pAAV-MCS-betaRARE-Luc vector. Addition of 0.5 and 1 micro molar all-trans retinoic acid significantly (P < 0.05) increased the activity of the pAAV-MCS-betaRARE-Luc reporter compared to cells transfected with the control reporter lacking a retinoic acid response element. Addition of 5 or 10 micro molar all-trans retinol stimulated a mild increase in reporter activity, however, the increase was not statistically significant. Based on these results we conclude that cumulus cells contain endogenously active retinoid receptors and may also be competent to synthesize retinoic acid using the precursor, retinol. These results also indirectly provide evidence that retinoids administered either in vivo previously or in vitro may have exerted a receptor-mediated effect on cumulus-granulosa cells.

Animals↗