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1
Lefebvre, Bruno, Céline Brand, Sébastien Flajollet, and Philippe Lefebvre. "Down-Regulation of the Tumor Suppressor Gene Retinoic Acid Receptor β2 through the Phosphoinositide 3-Kinase/Akt Signaling Pathway." Molecular Endocrinology 20, no. 9 (September 1, 2006): 2109–21. http://dx.doi.org/10.1210/me.2005-0321.
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Abstract The retinoic acid receptor β2 (RARβ2) is a potent, retinoid-inducible tumor suppressor gene, which is a critical molecular relay for retinoid actions in cells. Its down-regulation, or loss of expression, leads to resistance of cancer cells to retinoid treatment. Up to now, no primary mechanism underlying the repression of the RARβ2 gene expression, hence affecting cellular retinoid sensitivity, has been identified. Here, we demonstrate that the phosphoinositide 3-kinase/Akt signaling pathway affects cellular retinoid sensitivity, by regulating corepressor recruitment to the RARβ2 promoter. Through direct phosphorylation of the corepressor silencing mediator for retinoic and thyroid hormone receptors (SMRT), Akt stabilized RAR/SMRT interaction, leading to an increased tethering of SMRT to the RARβ2 promoter, decreased histone acetylation, down-regulation of the RARβ2 expression, and impaired cellular differentiation in response to retinoid. The phosphoinositide 3-kinase/Akt signaling pathway, an important modulator of cellular survival, has thus a direct impact on cellular retinoid sensitivity, and its deregulation may be the triggering event in retinoid resistance of cancer cells.
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Mehta, Kapil, Teresa McQueen, Taghi Manshouri, Michael Andreeff, Steven Collins, and Maher Albitar. "Involvement of Retinoic Acid Receptor-α–Mediated Signaling Pathway in Induction of CD38 Cell-Surface Antigen." Blood 89, no. 10 (May 15, 1997): 3607–14. http://dx.doi.org/10.1182/blood.v89.10.3607.
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Abstract Human leukocyte antigen CD38, a 45-kD single-chain, transmembrane glycoprotein, is a bifunctional ectoenzyme that participates in signal transduction pathways involved in the regulation of cell growth and differentiation. In this study, we demonstrate the nature of retinoid receptors involved in retinoic acid–induced expression of CD38 protein in the human myeloblastic leukemia cell line HL-60. We used a variant HL-60 cell line, HL-60R, in which retinoid receptor function has been abrogated by a trans-dominant negative mutation. We introduced the normal retinoic acid receptors (RAR)-α, -β, and -γ or retinoid X receptor (RXR)-α into HL-60R cells by retroviral vector-mediated gene transfer. Based on experiments using these cell lines and receptor-specific synthetic retinoids that preferentially bind to one of the RARs or RXRs, we conclude that RAR-α is involved in retinoid-induced CD38 expression in HL-60 cells. Further evidence included our demonstration that blocking of RAR-α with the antagonist Ro 41-5253 completely suppressed the retinoid-induced expression of CD38 mRNA transcript and the production of CD38 protein in HL-60 cells. Various tissues from transgenic mice that expressed an antisense construct of RAR-α lacked or produced very low levels of CD38. As expected, the tissues from transgenic mice contained 50% to 80% reduced levels of RAR-α. These results suggest that regulation of CD38 expression, both in vitro and in vivo, is under the direct control of RAR-α retinoid receptors.
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Mehta, Kapil, Teresa McQueen, Taghi Manshouri, Michael Andreeff, Steven Collins, and Maher Albitar. "Involvement of Retinoic Acid Receptor-α–Mediated Signaling Pathway in Induction of CD38 Cell-Surface Antigen." Blood 89, no. 10 (May 15, 1997): 3607–14. http://dx.doi.org/10.1182/blood.v89.10.3607.3607_3607_3614.
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Human leukocyte antigen CD38, a 45-kD single-chain, transmembrane glycoprotein, is a bifunctional ectoenzyme that participates in signal transduction pathways involved in the regulation of cell growth and differentiation. In this study, we demonstrate the nature of retinoid receptors involved in retinoic acid–induced expression of CD38 protein in the human myeloblastic leukemia cell line HL-60. We used a variant HL-60 cell line, HL-60R, in which retinoid receptor function has been abrogated by a trans-dominant negative mutation. We introduced the normal retinoic acid receptors (RAR)-α, -β, and -γ or retinoid X receptor (RXR)-α into HL-60R cells by retroviral vector-mediated gene transfer. Based on experiments using these cell lines and receptor-specific synthetic retinoids that preferentially bind to one of the RARs or RXRs, we conclude that RAR-α is involved in retinoid-induced CD38 expression in HL-60 cells. Further evidence included our demonstration that blocking of RAR-α with the antagonist Ro 41-5253 completely suppressed the retinoid-induced expression of CD38 mRNA transcript and the production of CD38 protein in HL-60 cells. Various tissues from transgenic mice that expressed an antisense construct of RAR-α lacked or produced very low levels of CD38. As expected, the tissues from transgenic mice contained 50% to 80% reduced levels of RAR-α. These results suggest that regulation of CD38 expression, both in vitro and in vivo, is under the direct control of RAR-α retinoid receptors.
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Murphy, Philip T., Gary Lynch, Stephen Bergin, John Quinn, Siobhan Glavey, Philip W. Murphy, and Paul Kennedy. "Strong Correlation Between CTLA-4 and LEF1 Gene Expression Levels in CLL: Targeting of the Wnt/β-Catenin Pathway May Adversely Affect CTLA-4 Expression and Function." Blood 128, no. 22 (December 2, 2016): 5571. http://dx.doi.org/10.1182/blood.v128.22.5571.5571.
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Abstract Recently published clinical trials have confirmed the effectiveness of anti-CD38 monoclonal antibody therapy in myeloma. Furthermore, in vitro studies of chronic lymphocytic leukaemia (CLL) cells suggest that CD38 expression can be enhanced by treatment with retinoid derivatives and thus may enhance the cytotoxic effects of anti-CD38 therapy. However, retinoids have been shown to have diverse effects on cellular function and we have previously shown that the retinoid drug acitretin upregulates CD38 expression while also reducing cell homing to the chemokine CXCL12 in primary CLL cells. To investigate possible key mechanisms for these effects, we purified CD20+ B cells from the peripheral blood of 20 CLL patients (9 previously treated, 11 untreated) and, using flow cytometry, measured percentage cell surface expression of CD38 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4, CD152). We also measured gene expression levels of the key retinoid receptor, stimulated by retinoic acid 6 (STRA6) and it's agonist, retinol-binding protein 4 (RBP4), as well as CTLA-4, cyclin D1 (CCND1) and the transcription factors, lymphoid enhancer factor 1 (LEF1) and signal transducer and activator of transcription 3 (STAT3) using RT-PCR. GAPDH was used as a reference gene. Mean percentage surface expression of CD38 and CTLA-4 was 21.96% and 45.25% respectively. Mean ∆CT gene expression levels of CCND1, CTLA-4, LEF1 and STAT3 were 12.03, 5.57 , 5.99 and 8.98 respectively. RBP4 and STRA6 gene expression levels were undetectable in all 20 patients. Gene expression of LEF1 showed significant correlations with CTLA-4 (rs=0.572, p=0.008), CCND1 (rs=0.61, p=0.004) and STAT3 (rs=0.587, p=0.006). There was also a significant correlation between gene expression of CCND1 and of STAT3 (r =0.499, p=0.025). No significant correlations were found between percentage surface expression of CTLA-4 and gene expression levels of either CTLA-4 or of LEF1. A weak negative correlation between percentage surface expression of CTLA-4 and of CD38 was not statistically significant. Comparing untreated and previously treated patients, there was no significant difference in gene expression levels of CTLA-4 and of LEF1 or in surface expression of CTLA-4. The failure to detect RBP4 and STRA6 gene expression in unstimulated peripheral blood CLL cells is evidence against an autocrine retinoid effect in CLL, although upregulation of STRA6 gene expression following stimulation by retinoids might be anticipated. The Wnt signalling pathway has been shown to be active in CLL, including aggressive disease subtypes, highlighting the potential benefits in targeting this pathway. Intriguingly, CTLA-4 expression, although found to be the most highly induced gene following treatment with recombinant Wnt-3a in melanoma cell lines, is associated with a favourable outcome in CLL, possibly by inhibiting cell proliferation and survival. In contrast, expression of LEF1, which is a direct target of the Wnt signalling pathway, is associated with disease progression in CLL. Our finding that CTLA-4 and LEF1 gene expression levels are strongly correlated suggests that further investigation of the relationship between CTLA-4 and the Wnt/β-Catenin pathway in CLL is required and that targeting of the Wnt/β-catenin pathway may have unwanted consequences on CTLA-4 expression and function. Disclosures Quinn: Celgene: Honoraria; Janssen Cilag: Honoraria.
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Aydemir, Gamze, Marta Domínguez, Angel R. de Lera, Johanna Mihaly, Dániel Törőcsik, and Ralph Rühl. "Apo-14´-Carotenoic Acid Is a Novel Endogenous and Bioactive Apo-Carotenoid." Nutrients 11, no. 9 (September 4, 2019): 2084. http://dx.doi.org/10.3390/nu11092084.
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Carotenoids can be metabolized to various apo-carotenoids and retinoids. Apo-15´-carotenoic acid (retinoic acid, RA) is a potent activator of the retinoic acid receptor (RAR) in its all-trans- (ATRA) and 9-cis- (9CRA) forms. In this study we show firstly, that apo-14´-carotenoic acid (A14CA), besides retinoic acids, is present endogenously and with increased levels in the human organism after carrot juice supplementation rich in β-carotene. All-trans-A14C (ATA14CA) is just a moderate activator of RAR-transactivation in reporter cell lines but can potently activate retinoic acid response element (RARE)-mediated signalling in DR5/RARE-reporter mice and potently increase retinoid-reporter target gene expression in ATA14CA-supplemented mice and treated MM6 cells. Further metabolism to all-trans-13,14-dihydroretinoic acid (ATDHRA) may be the key for its potent effects on retinoid target gene activation in ATA14CA-treated MM6 cells and in liver of supplemented mice. We conclude that besides RAs, there are alternative ways to activate RAR-response pathways in the mammalian organism. ATA14CA alone and in combination with its metabolite ATDHRA may be an alternative pathway for potent RAR-mediated signalling.
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van der Wees, J., J. G. Schilthuis, C. H. Koster, H. Diesveld-Schipper, G. E. Folkers, P. T. van der Saag, M. I. Dawson, K. Shudo, B. van der Burg, and A. J. Durston. "Inhibition of retinoic acid receptor-mediated signalling alters positional identity in the developing hindbrain." Development 125, no. 3 (February 1, 1998): 545–56. http://dx.doi.org/10.1242/dev.125.3.545.
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Retinoids regulate gene expression via nuclear retinoic acid receptors, the RARs and RXRs. To investigate the functions of retinoid receptors during early neural development, we expressed a dominant negative RARbeta in early Xenopus embryos. We obtained evidence that dominant negative RARbeta specifically inhibits RAR/RXR heterodimer-mediated, but not RXR homodimer-mediated, transactivation. Both all-trans- and 9-cis-RA-induced teratogenesis were, however, efficiently opposed by ectopic expression of dominant negative RARbeta, indicating that only RAR/RXR transactivation is required for retinoid teratogenesis by each of these ligands. Experiments with two RXR-selective ligands confirmed that activation of RXR homodimers does not cause retinoid teratogenesis. Dominant negative RARbeta thus specifically interferes with the retinoid signalling pathway that is responsible for retinoid teratogenesis. Dominant negative RARbeta-expressing embryos had a specific developmental phenotype leading to disorganization of the hindbrain. Mauthner cell multiplications in the posterior hindbrain, and (both anteriorly and posteriorly) expanded Krox-20 expression domains indicated (partial) transformation of a large part of the hindbrain into (at least partial) rhombomere 3, 4 and/or 5 identity. In contrast, the fore- and midbrain and spinal cord appeared to be less affected. These data indicate that RARs play a role in patterning the hindbrain.
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Park, Dorothy J., Peter T. Vuong, Sven de Vos, Dan Douer, and H. Phillip Koeffler. "Comparative analysis of genes regulated by PML/RARα and PLZF/RARα in response to retinoic acid using oligonucleotide arrays." Blood 102, no. 10 (November 15, 2003): 3727–36. http://dx.doi.org/10.1182/blood-2003-02-0412.
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Abstract Acute promyelocytic leukemia (APL) is associated with chromosomal translocations involving retinoic acid receptor α (RARα) and its fusion partners including promyelocytic leukemia (PML) and promyelocytic leukemia zinc finger (PLZF). Using oligonucleotide arrays, we examined changes in global gene expression mediated by the ectopic expression of either PML/RARα (retinoid-sensitive) or PLZF/RARα (retinoid-resistant) in U937 cells. Of more than 5000 genes analyzed, 16 genes were commonly up-regulated, and 57 genes were down-regulated by both fusion proteins suggesting their role in the APL phenotype. In our APL model, for example, TNFAIP2, TNFR2, ELF4, RARγ, and HoxA1 were down-regulated by both fusion proteins in the absence of retinoic acid (RA). RA strongly up-regulated these genes in PML/RARα, but not in PLZF/RARα expressing U937 cells. Expression studies in NB4, retinoid-resistant NB4-R2, normal human CD34+ cells, and APL patient samples strongly suggest their role in the regulation of granulocytic differentiation. Furthermore, combined treatment with tumor necrosis factor α (TNFα) and RA synergistically enhanced granulocytic differentiation in NB4 cells but not in NB4-R2 cells. Our data indicate that APL pathogenesis and retinoid-induced granulocytic differentiation of APL cells involve genes in the cell death pathway, and that cooperation between the RA and TNFα signaling pathways exists. Targeting both the retinoid-dependent differentiation and the cell death pathways may improve leukemic therapy, especially in retinoid-resistant acute myeloid leukemia. (Blood. 2003;102:3727-3736)
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Quere, Ronan, Aurelie Baudet, Bruno Cassinat, Gerald Bertrand, Jacques Marti, Laurent Manchon, David Piquemal, Christine Chomienne, and Therese Commes. "Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity." Blood 109, no. 10 (January 11, 2007): 4450–60. http://dx.doi.org/10.1182/blood-2006-10-051086.
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AbstractDisease relapse sometimes occurs after acute promyelocytic leukemia (APL) therapy with all-trans retinoic acid (ATRA). Among the diagnostic parameters predicting relapse, heterogeneity in the in vitro differentiation rate of blasts is an independent factor. To identify biologic networks involved in resistance, we conducted pharmacogenomic studies in APL blasts displaying distinct ATRA sensitivities. Although the expression profiles of genes invested in differentiation were similarly modulated in low- and high-sensitive blasts, low-sensitive cells showed higher levels of transcription of ATRA-target genes, transcriptional regulators, chromatin remodelers, and transcription factors. In opposition, only high-sensitive blasts expressed the CYP26A1 gene, encoding the p450 cytochrome which is known to be involved in retinoic acid catabolism. In NB4 cells, ATRA treatment activates a novel signaling pathway, whereby interleukin-8 stimulates the expression of the homeobox transcription factor HOXA10v2, an effective enhancer of CYP26A1 transcription. These data were corroborated in primary APL cells, as maturation levels correlated with CYP26A1 expression. Treatment with a retinoic acid metabolism blocking agent (RAMBA) results in high-nucleoplasmic concentrations of retinoid and growth of NB4-resistant subclones. Hence, for APL blasts associated with poor prognosis, the low CYP26A1 expression may explain high risk of resistance installation, by increased retinoid pressure. Pharmacogenomic profiles of genes involved in retinoid acid metabolism may help to optimize anticancer therapies, including retinoids.
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Lehrke, Ingo, Matthias Schaier, Kerstin Schade, Christian Morath, Ruediger Waldherr, Eberhard Ritz, and Juergen Wagner. "Retinoid receptor-specific agonists alleviate experimental glomerulonephritis." American Journal of Physiology-Renal Physiology 282, no. 4 (April 1, 2002): F741—F751. http://dx.doi.org/10.1152/ajprenal.00026.2001.
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Retinoids are potent antiproliferative and anti-inflammatory compounds. We previously demonstrated that the natural pan-agonists all- trans retinoic acid (RA) and 13- cis RA efficiently preserve renal structure and function in rat mesangioproliferative glomerulonephritis. We examine effects of synthetic retinoid receptor-specific agonists 1) to identify common and receptor subtype-specific pathways in this model and 2) to characterize effects of retinoids on the renal endothelin (ET) system. Vehicle-injected control rats were compared with rats treated with daily subcutaneous injections of agonists specific for retinoid A (Ro-137410) and retinoid X (Ro-257386) receptors and the complex anti-activator protein-1 active retinoid BMS-453 7 days after induction of anti-Thy1.1 nephritis ( n = 7–9/group). The different retinoids lowered glomerular ET-1 and ET type A and B receptor gene expression in control and nephritic rats with comparable efficacy. Reduction of glomerular c-Fos and GATA-2 mRNA expression levels suggests downregulation of transcription factors required for ET expression. The different retinoids were similar in their action on the glomerular capillary occlusion score, number of total glomerular cells, and glomerular infiltrating macrophage count. They differed in their ability to normalize blood pressure (Ro-257386 > BMS-453 > arotinoid), albuminuria (BMS-453 > Ro-257386 > arotinoid), and creatinine clearance (arotinoid > BMS-453 > Ro-257386). No signs of toxicity were observed. We conclude that all retinoid agonists with different subtype specificity are highly efficient in reducing renal damage and proliferation of mesangial cells. Retinoid X and A receptor-specific pathways are apparently involved in the antiproliferative, anti-inflammatory, and anti-ET action. Further studies are indicated to define the potential use of retinoid agonists in inflammatory renal disease.
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Hoffman, Lisa M., Kamal Garcha, Konstantina Karamboulas, Matthew F. Cowan, Linsay M. Drysdale, William A. Horton, and T. Michael Underhill. "BMP action in skeletogenesis involves attenuation of retinoid signaling." Journal of Cell Biology 174, no. 1 (July 3, 2006): 101–13. http://dx.doi.org/10.1083/jcb.200604150.
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The bone morphogenetic protein (BMP) and growth and differentiation factor (GDF) signaling pathways have well-established and essential roles within the developing skeleton in coordinating the formation of cartilaginous anlagen. However, the identification of bona fide targets that underlie the action of these signaling molecules in chondrogenesis has remained elusive. We have identified the gene for the retinoic acid (RA) synthesis enzyme Aldh1a2 as a principal target of BMP signaling; prochondrogenic BMPs or GDFs lead to attenuation of Aldh1a2 expression and, consequently, to reduced activation of the retinoid signaling pathway. Consistent with this, antagonism of retinoid signaling phenocopies BMP4 action, whereas RA inhibits the chondrogenic stimulatory activity of BMP4. BMP4 also down-regulates Aldh1a2 expression in organ culture and, consistent with this, Aldh1a2 is actively excluded from the developing cartilage anlagens. Collectively, these findings provide novel insights into BMP action and demonstrate that BMP signaling governs the fate of prechondrogenic mesenchyme, at least in part, through regulation of retinoid signaling.
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Baleato, R. M., R. J. Aitken, and S. D. Roman. "244.Interaction between bone morphogenetic protein 4 and retinoid signalling in mouse spermatogenesis." Reproduction, Fertility and Development 16, no. 9 (2004): 244. http://dx.doi.org/10.1071/srb04abs244.
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Vitamin A (retinol, or ROL) is also essential for normal spermatogenesis in the rat and mouse. Vitamin A-deficient (VAD) rodents suffer various disorders including blindness and male infertility. The molecular mechanisms leading to infertility in vitamin A deficient rodents have never been fully elucidated. Following prolonged vitamin A withdrawal the only germ cells remaining in the VAD rodent testis are stem cell spermatogonia, type A1 spermatogonia, and a few preleptotene spermatocytes. Supplementing the diet of these animals with retinoic acid (RA) alleviates all symptoms of vitamin A deficiency, with the exception of sight and spermatogenesis. It is not until VAD animals are re-administered ROL through the diet, or RA is injected in repeated high doses directly into the testis, that normal spermatogenic function is restored. Here we report an interaction, in germ cells, between the Bone Morphogenetic Protein (BMP) 4 and retinoid signalling pathways that may help explain the molecular mechanics of vitamin A deficiency. We localised BMP4 gene expression to adult germ cells, in particular spermatogonia, at both the mRNA and protein level. We generated VAD mice and found that in the absence of retinoids in vivo, bmp4 gene expression was significantly upregulated in the testis. We also observed that the expression of bmp4 is downregulated by retinoid treatment in germ cells isolated from vitamin A sufficient mice. Expression of bmp4 mRNA in isolated spermatogonia was more sensitive to ROL rather than RA. Our results may reflect a direct requirement for ROL by germ cells for the resumption of spermatogenesis in VAD animals that involves the regulation of BMP4 expression. Furthermore our observations suggest that retinoid signalling in germ cells is different to that observed in somatic cells, and may provide insights into the role of retinoids in spermatogenesis.
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Lattuada, Debora, Paola Viganó, Silvia Mangioni, Jenny Sassone, Stefania Di Francesco, Michele Vignali, and Anna Maria Di Blasio. "Accumulation of Retinoid X Receptor-α in Uterine Leiomyomas Is Associated with a Delayed Ligand-Dependent Proteasome-Mediated Degradation and an Alteration of Its Transcriptional Activity." Molecular Endocrinology 21, no. 3 (March 1, 2007): 602–12. http://dx.doi.org/10.1210/me.2006-0206.
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Abstract An alteration of the retinoid pathway can influence the development of uterine leiomyomas in animal models, and retinoids have shown efficacy in inhibiting the growth of this benign tumor both in vitro and in vivo. However, the underlying mechanisms and biological implications are unclear. The present study was based on the demonstration of an accumulation of full-length retinoid X receptor α (RXRα) in leiomyomas that was not associated with a modification of its gene expression. This accumulation was shown to increase the transcription of the RXR-responsive gene cellular retinoic acid binding protein II (CRABP-II) and to be linked to the cellular redistribution of the receptor and to its retarded degradation via the ubiquitin/proteasome pathway. Accordingly, treatment with a specific proteasome inhibitor but not with protease inhibitors strongly inhibited the degradation of full-length RXRα in cells deriving from both myometrium and leiomyoma, but the formation of RXRα/ubiquitin conjugates was differentially regulated between the two cell types. Moreover, full-length RXRα accumulated in leiomyomas was abnormally phosphorylated at serine/threonine residues relative to myometrial tissue. The ligand to RXRα, 9-cis-retinoic acid, induced the receptor breakdown in smooth muscle cells deriving from both normal and tumor tissue, whereas a MAPK-specific inhibitor was able to reduce RXRα levels only in leiomyoma cells. These results suggest that switching of the ubiquitin/proteasome-dependent degradation of RXRα by phosphorylation in leiomyomas may be responsible for the accumulation of the receptor and the consequent dysregulation of retinoic acid target genes. The ability of retinoids to modify this molecular alteration may be the rationale for their use in the treatment of leiomyomas.
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Jiao, Xiaoyang, Rang Liu, Jiali Huang, Lichun Lu, Zibo Li, Liyan Xu, and Enmin Li. "Cellular Retinoic-Acid Binding Protein 2 in Solid Tumor." Current Protein & Peptide Science 21, no. 5 (June 2, 2020): 507–16. http://dx.doi.org/10.2174/1389203721666200203150721.
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The retinoic acid (RA) signaling pathway is crucial for many biological processes. The RA transporter, Cellular Retinoic-Acid Binding Protein 2 (CRABP2), is abnormally expressed in various tumor types. CRABP2 presents significant effects on tumorous behaviors and functions, including cell proliferation, apoptosis, invasion, migration, metastasis, and angiogenesis. The tumorigenesis mechanism of CRABP2, as both suppressor and promotor, is complicated, therefore, there remains the need for further investigation. Elucidating the regulating mechanisms in a specific stage of the tumor could facilitate CRABP2 to be a biomarker in cancer diagnosis and prognosis. Besides, clarifying the pathways of CRABP2 in cancer development will contribute to the gene-targeted therapy. In this review, we summarized the expression, distribution, and mechanism of CRABP2 in solid tumors. Illuminating the CRABP2 signaling pathway may benefit understanding the retinoid signaling pathway, providing a useful biomarker for future clinical trials.
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Benedetti, L., F. Grignani, BM Scicchitano, AM Jetten, D. Diverio, F. Lo Coco, G. Avvisati, et al. "Retinoid-induced differentiation of acute promyelocytic leukemia involves PML-RARalpha-mediated increase of type II transglutaminase." Blood 87, no. 5 (March 1, 1996): 1939–50. http://dx.doi.org/10.1182/blood.v87.5.1939.1939.
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Abstract All-trans retinoic acid (t-RA) administration leads to complete remission in acute promyelocytic leukemia (APL) patients by inducing growth arrest and differentiation of the leukemic clone. In the present study, we show that t-RA treatment dramatically induced type II transglutaminase (type II TGase) expression in cells carrying the t(15;17) translocation and expressing the PML-RARalpha product such as the APL-derived NB4 cell line and fresh leukemic cells from APL patients. This induction correlated with t-RA-induced growth arrest, granulocytic differentiation, and upregulation of the leukocyte adherence receptor beta subunit (CD18) gene expression. The increase in type II TGase was not abolished by cycloheximide treatment, suggesting that synthesis of a protein intermediate was not required for the induction. t-RA did not significantly alter the rate of growth arrest and did not stimulate differentiation and type II TGase activity in NB4.306 cells, a t-RA-resistant subclone of the NB4 cell line, or in leukemic cells derived from two patients morphologically defined as APL but lacking the t(15;17). However, in NB4.306 cells, t-RA treatment was able to increase CD18 mRNA expression in a manner similar to NB4 cells. The molecular mechanisms involved in the induction of these genes were investigated. In NB4 cells, using novel receptor-selective ligands such as 9-cis-RA, TTNPB, AM580, and SR11217, we found that RAR- and RARalpha- selective retinoids were able to induce growth arrest, granulocytic differentiation, and type II TGase, whereas the RXR-selective retinoid SR11217 was inactive. Moreover, an RAR alpha-antagonist completely inhibited the expression of type II TGase and CD18 induced by these selective retinoids in NB4 cells. In NB4.306 cells, an RARalpha- dependent signaling pathway was found involved in the modulation of CD18 expression. In addition, expression of the PML-RARalpha gene in myeloid U937 precursor cells resulted in the ability of these cells to induce type II TGase in response to t-RA. On the basis of these results we hypothesize a specific involvement of a signaling pathway involving PML-RAR alpha for the induction of growth arrest, granulocytic differentiation, and type II TGase by retinoids in APL cells.
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Benedetti, L., F. Grignani, BM Scicchitano, AM Jetten, D. Diverio, F. Lo Coco, G. Avvisati, et al. "Retinoid-induced differentiation of acute promyelocytic leukemia involves PML-RARalpha-mediated increase of type II transglutaminase." Blood 87, no. 5 (March 1, 1996): 1939–50. http://dx.doi.org/10.1182/blood.v87.5.1939.bloodjournal8751939.
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All-trans retinoic acid (t-RA) administration leads to complete remission in acute promyelocytic leukemia (APL) patients by inducing growth arrest and differentiation of the leukemic clone. In the present study, we show that t-RA treatment dramatically induced type II transglutaminase (type II TGase) expression in cells carrying the t(15;17) translocation and expressing the PML-RARalpha product such as the APL-derived NB4 cell line and fresh leukemic cells from APL patients. This induction correlated with t-RA-induced growth arrest, granulocytic differentiation, and upregulation of the leukocyte adherence receptor beta subunit (CD18) gene expression. The increase in type II TGase was not abolished by cycloheximide treatment, suggesting that synthesis of a protein intermediate was not required for the induction. t-RA did not significantly alter the rate of growth arrest and did not stimulate differentiation and type II TGase activity in NB4.306 cells, a t-RA-resistant subclone of the NB4 cell line, or in leukemic cells derived from two patients morphologically defined as APL but lacking the t(15;17). However, in NB4.306 cells, t-RA treatment was able to increase CD18 mRNA expression in a manner similar to NB4 cells. The molecular mechanisms involved in the induction of these genes were investigated. In NB4 cells, using novel receptor-selective ligands such as 9-cis-RA, TTNPB, AM580, and SR11217, we found that RAR- and RARalpha- selective retinoids were able to induce growth arrest, granulocytic differentiation, and type II TGase, whereas the RXR-selective retinoid SR11217 was inactive. Moreover, an RAR alpha-antagonist completely inhibited the expression of type II TGase and CD18 induced by these selective retinoids in NB4 cells. In NB4.306 cells, an RARalpha- dependent signaling pathway was found involved in the modulation of CD18 expression. In addition, expression of the PML-RARalpha gene in myeloid U937 precursor cells resulted in the ability of these cells to induce type II TGase in response to t-RA. On the basis of these results we hypothesize a specific involvement of a signaling pathway involving PML-RAR alpha for the induction of growth arrest, granulocytic differentiation, and type II TGase by retinoids in APL cells.
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Shao, Wenlin, Laura Benedetti, William W. Lamph, Clara Nervi, and Wilson H. Miller. "A Retinoid-Resistant Acute Promyelocytic Leukemia Subclone Expresses a Dominant Negative PML-RARα Mutation." Blood 89, no. 12 (June 15, 1997): 4282–89. http://dx.doi.org/10.1182/blood.v89.12.4282.
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Abstract The unique t(15; 17) of acute promyelocytic leukemia (APL) fuses the PML gene with the retinoic acid receptor α (RARα) gene. Although retinoic acid (RA) inhibits cell growth and induces differentiation in human APL cells, resistance to RA develops both in vitro and in patients. We have developed RA-resistant subclones of the human APL cell line, NB4, whose nuclear extracts display altered RA binding. In the RA-resistant subclone, R4, we find an absence of ligand binding of PML-RARα associated with a point mutation changing a leucine to proline in the ligand-binding domain of the fusion PML-RARα protein. In contrast to mutations in RARα found in retinoid-resistant HL60 cells, in this NB4 subclone, the coexpressed RARα remains wild-type. In vitro expression of a cloned PML-RARα with the observed mutation in R4 confirms that this amino acid change causes the loss of ligand binding, but the mutant PML-RARα protein retains the ability to heterodimerize with RXRα and thus to bind to retinoid response elements (RAREs). This leads to a dominant negative block of transcription from RAREs that is dose-dependent and not relieved by RA. An unrearranged RARα engineered with this mutation also lost ligand binding and inhibited transcription in a dominant negative manner. We then found that the mutant PML-RARα selectively alters regulation of gene expression in the R4 cell line. R4 cells have lost retinoid-regulation of RXRα and RARβ and the RA-induced loss of PML-RARα protein seen in NB4 cells, but retain retinoid-induction of CD18 and CD38. Thus, the R4 cell line provides data supporting the presence of an RARα-mediated pathway that is independent from gene expression induced or repressed by PML-RARα. The high level of retinoid resistance in vitro and in vivo of cells from some relapsed APL patients suggests similar molecular changes may occur clinically.
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ALVAREZ, Rosa, MaLuz CHECA, Sonia BRUN, Octavi VI±AS, Teresa MAMPEL, Roser IGLESIAS, Marta GIRALT, and Francesc VILLARROYA. "Both retinoic-acid-receptor- and retinoid-X-receptor-dependent signalling pathways mediate the induction of the brown-adipose-tissue-uncoupling-protein-1 gene by retinoids." Biochemical Journal 345, no. 1 (December 17, 1999): 91–97. http://dx.doi.org/10.1042/bj3450091.
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The intracellular pathways and receptors mediating the effects of retinoic acid (RA) on the brown-fat-uncoupling-protein-1 gene (ucp-1) have been analysed. RA activates transcription of ucp-1 and the RA receptor (RAR) is known to be involved in this effect. However, co-transfection of an expression vector for retinoid-X receptor (RXR) increases the action of 9-cis RA but not the effects of all-trans RA on the ucp-1 promoter in brown adipocytes. Either RAR-specific {p-[(E)-2-(5,6,7,8,-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid} or RXR-specific [isopropyl-(E,E)-(R,S)-11-methoxy-3,7,11-trimethyldodeca-2,4-dienoate, or methoprene] synthetic compounds increase the expression of UCP-1 mRNA and the activity of chloramphenicol acetyltransferase expression vectors driven by the ucp-1 promoter. The RXR-mediated action of 9-cis RA requires the upstream enhancer region at -2469/-2318 in ucp-1. During brown-adipocyte differentiation RXRα and RXRγ mRNA expression is induced in parallel with UCP-1 mRNA, whereas the mRNA for the three RAR subtypes, α, β and γ, decreases. Co-transfection of murine expression vectors for the different RAR and RXR subtypes indicates that RARα and RARβ as well as RXRα are the major retinoid-receptor subtypes capable of mediating the responsiveness of ucp-1 to retinoids. It is concluded that the effects of retinoids on ucp-1 transcription involve both RAR- and RXR-dependent signalling pathways. The responsiveness of brown adipose tissue to retinoids in vivo relies on a complex combination of the capacity of RAR and RXR subtypes to mediate ucp-1 induction and their distinct expression in the differentiated brown adipocyte.
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Tate, B. F., G. Allenby, R. Janocha, S. Kazmer, J. Speck, L. J. Sturzenbecker, P. Abarzúa, A. A. Levin, and J. F. Grippo. "Distinct binding determinants for 9-cis retinoic acid are located within AF-2 of retinoic acid receptor alpha." Molecular and Cellular Biology 14, no. 4 (April 1994): 2323–30. http://dx.doi.org/10.1128/mcb.14.4.2323.
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Retinoids exert their physiological action by interacting with two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which regulate gene expression by forming transcriptionally active heterodimeric RAR/RXR or homodimeric RXR/RXR complexes on DNA. Retinoid receptor activity resides in several regions, including the DNA and ligand binding domains, a dimerization interface, and both a ligand-independent (AF-1) and a ligand-dependent (AF-2) transactivation function. While 9-cis retinoic acid (RA) alone is the cognate ligand for the RXRs, both 9-cis RA and all-trans RA (t-RA) compete for binding with high affinity to the RARs. This latter observation suggested to us that the two isomers may interact with a common binding site. Here we report that RAR alpha has two distinct but overlapping binding sites for 9-cis RA and t-RA. Truncation of a human RAR alpha to 419 amino acids yields a receptor that binds both t-RA and 9-cis RA with high affinity, but truncation to amino acid 404 yields a mutant receptor that binds only t-RA with high affinity. Remarkably, this region also defines a C-terminal boundary for AF-2, as addition of amino acids 405 to 419 restores receptor-mediated gene activity to a truncated human RAR alpha lacking this region. It is interesting to speculate that binding of retinoid stereoisomers to unique sites within an RAR may function with AF-2 to cause differential activation of retinoid-responsive gene pathways.
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Tate, B. F., G. Allenby, R. Janocha, S. Kazmer, J. Speck, L. J. Sturzenbecker, P. Abarzúa, A. A. Levin, and J. F. Grippo. "Distinct binding determinants for 9-cis retinoic acid are located within AF-2 of retinoic acid receptor alpha." Molecular and Cellular Biology 14, no. 4 (April 1994): 2323–30. http://dx.doi.org/10.1128/mcb.14.4.2323-2330.1994.
Full textAbstract:
Retinoids exert their physiological action by interacting with two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which regulate gene expression by forming transcriptionally active heterodimeric RAR/RXR or homodimeric RXR/RXR complexes on DNA. Retinoid receptor activity resides in several regions, including the DNA and ligand binding domains, a dimerization interface, and both a ligand-independent (AF-1) and a ligand-dependent (AF-2) transactivation function. While 9-cis retinoic acid (RA) alone is the cognate ligand for the RXRs, both 9-cis RA and all-trans RA (t-RA) compete for binding with high affinity to the RARs. This latter observation suggested to us that the two isomers may interact with a common binding site. Here we report that RAR alpha has two distinct but overlapping binding sites for 9-cis RA and t-RA. Truncation of a human RAR alpha to 419 amino acids yields a receptor that binds both t-RA and 9-cis RA with high affinity, but truncation to amino acid 404 yields a mutant receptor that binds only t-RA with high affinity. Remarkably, this region also defines a C-terminal boundary for AF-2, as addition of amino acids 405 to 419 restores receptor-mediated gene activity to a truncated human RAR alpha lacking this region. It is interesting to speculate that binding of retinoid stereoisomers to unique sites within an RAR may function with AF-2 to cause differential activation of retinoid-responsive gene pathways.
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Shetty, Shoba, Maria A. Ramos-Roman, You-Ree Cho, Jonathan Brown, Jorge Plutzky, Eric S. Muise, Jay D. Horton, Philipp E. Scherer, and Elizabeth J. Parks. "Enhanced Fatty Acid Flux Triggered by Adiponectin Overexpression." Endocrinology 153, no. 1 (January 1, 2012): 113–22. http://dx.doi.org/10.1210/en.2011-1339.
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Adiponectin overexpression in mice increases insulin sensitivity independent of adiposity. Here, we combined stable isotope infusion and in vivo measurements of lipid flux with transcriptomic analysis to characterize fatty acid metabolism in transgenic mice that overexpress adiponectin via the aP2-promoter (ADNTg). Compared with controls, fasted ADNTg mice demonstrated a 31% reduction in plasma free fatty acid concentrations (P = 0.008), a doubling of ketones (P = 0.028), and a 68% increase in free fatty acid turnover in plasma (15.1 ± 1.5 vs. 25.3 ± 6.8 mg/kg · min, P = 0.011). ADNTg mice had 2-fold more brown adipose tissue mass, and triglyceride synthesis and turnover were 5-fold greater in this organ (P = 0.046). Epididymal white adipose tissue was slightly reduced, possibly due to the approximately 1.5-fold increase in the expression of genes involved in oxidation (peroxisome proliferator-activated receptor α, peroxisome proliferator-activated receptor-γ coactivator 1α, and uncoupling protein 3). In ADNTg liver, lipogenic gene expression was reduced, but there was an unexpected increase in the expression of retinoid pathway genes (hepatic retinol binding protein 1 and retinoic acid receptor beta and adipose Cyp26A1) and liver retinyl ester content (64% higher, P < 0.02). Combined, these data support a physiological link between adiponectin signaling and increased efficiency of triglyceride synthesis and hydrolysis, a process that can be controlled by retinoids. Interactions between adiponectin and retinoids may underlie adiponectin's effects on intermediary metabolism.
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Ferlosio, Amedeo, Elena Doldo, Sara Agostinelli, Gaetana Costanza, Federica Centofanti, Angelo Sidoni, and Augusto Orlandi. "Cellular retinol binding protein 1 transfection reduces proliferation and AKT-related gene expression in H460 non-small lung cancer cells." Molecular Biology Reports 47, no. 9 (September 2020): 6879–86. http://dx.doi.org/10.1007/s11033-020-05744-5.
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Abstract In recent years, new treatments with novel action mechanisms have been explored for advanced non-small cell lung cancer (NSCLC). Retinoids promote cancer cell differentiation and death and their trafficking and action is mediated from specific cytoplasmic and nuclear receptors, respectively. The purpose of this study was to investigate the effect of Cellular retinol binding protein-1 (CRBP-1) transfection in H460 human NSCLC cell line, normally not expressing CRBP-1. H460 cells were transfected by using a vector pTargeT Mammalian expression system carrying the whole sequence of CRBP-1 gene. For proliferation and apoptosis studies, cells were treated with different concentrations of all-trans Retinoic Acid (atRA) and retinol. AKT-related gene expression was analyzed by using western blot and Signosis array and results analysed by one-way analysis of variance (ANOVA) or by t-student test. CRBP-1+ showed reduced proliferation and viability in basal condition and after atRA treatment when compared to empty-transfected H460 cells. Reduced proliferation in CRBP-1+ H460 cells associated to the down-regulation of pAKT/pERK/pEGFR-related genes. In particular, gene array documented the down-regulation of AKT and Stat-3-related genes, including M-Tor, Akt1, Akt2, Akt3, Foxo1, p27, Jun. Restoration of CRBP-1 expression in H460 cells reduced proliferation and viability in both basal condition and after atRA treatment, likely by down-regulating AKT-related gene level. Further studies are needed to better clarify how those CRBP-1-related intracellular pathways contribute to counteract NSCLC progression in order to suggest a potential tool to improve efficacy of retinoid anti lung cancer adjuvant therapy.
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Wertz, Karin, Nicole Seifert, Petra Buchwald Hunziker, Georges Riss, Adrian Wyss, Willi Hunziker, and Regina Goralczyk. "β-Carotene interference with UVA-induced gene expression by multiple pathways." Pure and Applied Chemistry 78, no. 8 (January 1, 2006): 1539–50. http://dx.doi.org/10.1351/pac200678081539.
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UVA exposure causes skin photoaging by singlet oxygen (1O2)-mediated induction of matrix metalloproteases (MMPs). We assessed whether β-carotene, a carotenoid known as 1O2 quencher and retinoic acid (RA) precursor, interferes with UVA-induced gene regulation and prevents UVA-induced gene regulation in HaCaT human keratinocytes. HaCaT cells accumulated β-carotene in a time- and dose-dependent manner. UVA irradiation massively reduced the cellular β-carotene contents. β-Carotene suppressed UVA induction of MMP-1, MMP-3, and MMP-10 - three major MMPs involved in photoaging. HaCaT cells produced weak retinoid activity from β-carotene, as demonstrated by mild up-regulation of retinoid receptor RARβ and activation of an RARE-dependent reporter gene. Of the 568 UVA-regulated genes, β-carotene reduced the UVA effect for 143, enhanced it for 180, and did not interact with UVA for 245 genes. The pathways regulated β-carotene in interaction with UVA were characterized by genes involved in growth factor signaling, stress response, apoptosis, cell cycle, extracellular matrix (ECM) degradation, tanning, and inflammation. In conclusion, β-carotene at physiological concentrations interacted with UVA effects by multiple mechanisms that included, but were not restricted to, 1O2 quenching. With our results, we provide a mechanistic basis for the long-known and clinically established photoprotective effects of β-carotene in human skin.
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Ross, Alexander W., Catriona A. Webster, Julian G. Mercer, Kim M. Moar, Francis J. Ebling, Sandrine Schuhler, Perry Barrett, and Peter J. Morgan. "Photoperiodic Regulation of Hypothalamic Retinoid Signaling: Association of Retinoid X Receptor γ with Body Weight." Endocrinology 145, no. 1 (January 1, 2004): 13–20. http://dx.doi.org/10.1210/en.2003-0838.
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Abstract This study reports novel events related to photoperiodic programming of the neuroendocrine hypothalamus. To investigate photoperiod-responsive genes, Siberian hamsters were maintained in long or short photoperiods that generate physiological states of obesity or leanness. Microarray expression analysis first identified CRBP1 as a photoperiod-responsive gene, and then further studies using in situ hybridization and immunocytochemistry revealed that expression levels of several related retinoid-signaling genes were modulated in response to photoperiod changes. Genes of the retinoid-signaling pathway, encoding nuclear receptors (RXR/RAR) and retinoid binding proteins (CRBP1 and CRABP2) are photoperiodically regulated in the dorsal tuberomamillary nucleus (DTM): Their expression is significantly lower in short photoperiods and parallels body weight decreases. Studies in pinealectomized hamsters confirm that the pineal melatonin rhythm is necessary for these seasonal changes, and studies in testosterone-treated hamsters reveal that these changes in gene expression are not the secondary consequence of photoperiod-induced changes in steroid levels. Comparative studies using Syrian hamsters, which show divergent seasonal body weight responses to Siberian hamsters when exposed to short photoperiods, showed a distinct pattern of changes in retinoid gene expression in the DTM in response to a change in photoperiod. We infer that the DTM may be an important integrating center for photoperiodic control of seasonal physiology and suggest that the changes in retinoid X receptor γ expression may be associated with seasonal changes in body weight and energy metabolism.
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Giannì, M., M. Terao, S. Sozzani, and E. Garattini. "Retinoic acid and cyclic AMP synergistically induce the expression of liver/bone/kidney-type alkaline phosphatase gene in L929 fibroblastic cells." Biochemical Journal 296, no. 1 (November 15, 1993): 67–77. http://dx.doi.org/10.1042/bj2960067.
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In L929 mouse fibroblastic cells, liver/bone/kidney type alkaline phosphatase (L/B/K-ALP) enzymic activity is induced by all-trans-retinoic acid at concentrations between 10(-6) and 10(-5) M. At lower concentrations, retinoic acid is incapable of inducing this enzymic activity per se, but increases cyclic AMP (cAMP)-mediated induction. This effect is observed after incubation of the retinoid with dibutyryl cAMP, 8-bromo cAMP or forskolin. The synergism is dependent on the order of addition of retinoic acid and the activator of the cAMP pathway. Contemporaneous addition of the two agents, or addition of cAMP prior to retinoic acid (but not addition of retinoic acid before cAMP), is necessary to produce this synergistic interaction. The synergism results in increased steady-state levels of L/B/K-ALP mRNA and it is the consequence of increased transcriptional activity of the gene. The expression of the mouse L/B/K-ALP gene is regulated by the presence of two leader exons, 1A and 1B, resulting in the synthesis of two alternatively spliced mRNAs that are different only in part of their 5′ untranslated region [Studer, Terao, Giannì and Garattini (1991) Biochem. Biophys. Res. Commun. 179, 1352-1360]. PCR amplification and nuclear run-on experiments performed using probes specific for each leader exon demonstrate that treatment of these cells with retinoic acid, forskolin or dibutyryl cAMP, and with the combination of the retinoid and one of the cAMP-elevating agents, leads to the accumulation of nascent and mature L/B/K-ALP mRNA containing exon 1B. The synergistic induction of the transcription of the L/B/K-ALP gene is well correlated with quantitative and qualitative changes of retinoic-acid-receptor mRNAs mediated by cAMP.
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Sanchez, Patricia Vanessa, Reid P. Bissonnette, Donald E. Tsai, and Martin Carroll. "Gene Expression Analysis of Bexarotene Differentiated Acute Myeloid Leukemias Identifies Known and Novel Gene Targets." Blood 112, no. 11 (November 16, 2008): 1199. http://dx.doi.org/10.1182/blood.v112.11.1199.1199.
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Abstract Despite advances in understanding the molecular pathogenesis of acute myeloid leukemia (AML), therapy for relapsed disease remains inadequate with high mortalities. Clinicians at the University of Pennsylvania have demonstrated that the FDA approved retinoid X receptor (RXR) agonist bexarotene (Targretin™) stimulates leukemic cell differentiation in a subset patents with relapsed AML leading to clinical responses. This underscores the importance of identifying the mechanism by which bexarotene induces differentiation in AML in order to enhance the efficacy of this therapeutic approach. To understand the role of bexarotene and RXR receptors in leukemic cell differentiation, we initially utilized a pharmacogenetic approach to study the effects of bexarotene on AML cell lines using combinations of bexarotene with other differentiation induction agents. These studies demonstrate that bexarotene induces myeloid differentiation in MOLM14, HL60, THP-1, and NB4 cell lines but not in the myeloblastic cell line KG1a. Combination treatment of AML cell lines with bexarotene in combination with all trans retinoic acid (ATRA) enhanced differentiation suggesting that the mechanism of action for bexarotene is through RARα (retinoic acid receptor)/RXRα heterodimer stimulation. Consistent with this, differentiation induced by the drug combination was effectively blocked by the RAR antagonist, LG100815 and partially blocked by the RXR antagonist, LG101208. In contrast, bexarotene does not cooperate with valproic acid, theophylline, the PPARγ agonist rosiglitazone, or the LXR agonist T0901317. Preliminary data from quantitative RT-PCR and Affymetrix microarray analysis of bexarotene responsive AML cell lines at 3, 6, 12, and 96 hours post treatment has identified a subset of genes potentially regulated by bexarotene. CEBPε, a transcription factor known to play a critical role in granulopoiesis and PIM-1, a known oncogenic transcription factor, were among the genes that were significantly upregulated after bexarotene treatment of AML cells. Analysis of the functional role of C/EBPε in retinoid induced differentiation will be presented. Overall, this data supports the hypothesis that bexarotene, like ATRA, induces myeloid differentiation through activation of a RAR/RXR heterodimeric partner. However, other data suggests the presence of RAR independent pathways of signaling. LG100268, a pure RXR agonist induced myeloid differentiaton although not as robustly as bexarotene. Analysis of RAR and RXR mRNA expression in AML cell lines demonstrates that bexarotene does not induce expression of RARβ or p21, known targets induced by ATRA during myeloid differentiation. Chromatin immunoprecipitation assays demonstrate RXRα occupancy at RARβ and p21 promoter regions containing retinoid response elements (RARE). However, expression of these genes does not correlate with bexarotene-induced differentiation. This data suggests that although their expression has been linked to ATRA responsiveness, induction of RARβ and p21 expression is not necessary for retinoid induced myeloid differentiation. In summary, bexarotene induces myeloid differentiation through RAR dependent and independent pathways. Further analysis of the signaling events necessary for induction of myeloid differentiation by bexarotene may allow for improved selection of patients with AML who will respond to bexarotene.
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Houle, Martin, Panagiotis Prinos, Angelo Iulianella, Nathalie Bouchard, and David Lohnes. "Retinoic Acid Regulation of Cdx1: an Indirect Mechanism for Retinoids and Vertebral Specification." Molecular and Cellular Biology 20, no. 17 (September 1, 2000): 6579–86. http://dx.doi.org/10.1128/mcb.20.17.6579-6586.2000.
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ABSTRACT Retinoic acid (RA) is required for diverse developmental programs, including vertebral specification. Both RA receptor disruption and excess RA result in homeotic transformations of the axial skeleton. These effects are believed to occur through altered expression ofHox genes, several of which have been demonstrated to be direct RA targets. Members of the cdx (caudal) homeobox gene family are also implicated in regulating Hoxexpression. Disruption of cdx1 results in vertebral homeotic transformations and alteration of Hox expression boundaries; similar homeosis is also observed in cdx2heterozygotes. In Xenopus, gain or loss of Cdx function affects vertebral morphogenesis through a mechanism that also correlates with altered Hox expression. Taken together with the finding of putative Cdx binding motifs in several Hoxpromoters, these data strongly support a role for Cdx members in direct regulation of expression of at least some Hox genes. Most retinoid-responsive Hox genes have not been demonstrated to be direct RA targets, suggesting that intermediaries are involved. Based on these findings, we hypothesized that one or morecdx members may transduce the effects of RA onHox transcription. Consistent with this, we present evidence that cdx1 is a direct RA target gene, suggesting an additional pathway for retinoid-dependent vertebral specification.
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Levi, Liraz, Tamar Ziv, Arie Admon, Berta Levavi-Sivan, and Esther Lubzens. "Insight into molecular pathways of retinal metabolism, associated with vitellogenesis in zebrafish." American Journal of Physiology-Endocrinology and Metabolism 302, no. 6 (March 15, 2012): E626—E644. http://dx.doi.org/10.1152/ajpendo.00310.2011.
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Retinal is the main retinoid stored in oviparous eggs of fish, amphibians, and reptiles, reaching the oocytes in association with vitellogenins, the yolk precursor proteins. During early presegmentation stages of zebrafish embryos, retinal is metabolized to retinoic acid (RA), which regulates genes involved in cell proliferation, differentiation, and tissue function and is therefore essential for normal embryonic development. While synthesis of vitellogenin and its regulation by 17β-estradiol (E2) were extensively investigated, pathways for retinal synthesis remain obscure. We determined the expression pattern of 46 candidate genes, aiming at identifying enzymes associated with retinal synthesis, ascertaining whether they were regulated by E2, and finding pathways that could fulfill the demand for retinoids during vitellogenesis. Genes associated with retinal synthesis were upregulated in liver ( rdh10, rdh13, sdr) and surprisingly also in intestine ( rdh13) and ovary ( rdh1, sdr), concomitantly with higher gene expression and synthesis of vitellogenins in liver but also in extrahepatic tissues, shown here for the first time. Vitellogenin synthesis in the ovary was regulated by E2. Gene expression studies suggest that elevated retinal synthesis in liver, intestine, and ovary also depends on cleavage of carotenoids (by Bcdo2 or Bmco1), but in the ovary it may also be contingent on higher uptake of retinol from the circulatory system (via Stra6) and retinol synthesis from retinyl esters (by Lpl). Decrease in oxidation (by Raldh2 or Raldh3) of retinal to RA and/or degradation of RA (by Cyp26a1) may also facilitate higher hepatic retinal levels. Together, these processes enable meeting the putative demands of retinal for binding to vitellogenins. Bioinformatic tools reveal multiple hormone response elements in the studied genes, suggesting complex and intricate regulation of these processes.
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Everaert, Bert R., Steven J. Van Laere, Robrecht Lembrechts, Vicky Y. Hoymans, Jean-Pierre Timmermans, and Christiaan J. Vrints. "Identification of Macrophage Genotype and Key Biological Pathways in Circulating Angiogenic Cell Transcriptome." Stem Cells International 2019 (May 2, 2019): 1–12. http://dx.doi.org/10.1155/2019/9545261.
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Background. Circulating angiogenic cells (CAC) have been identified as important regulators of vascular biology. However, there is still considerable debate about the genotype and function of CAC. Methods and Results. Data from publicly available gene expression data sets were used to analyse the transcriptome of in vitro cultured CAC (CACiv). Genes and pathways of interest were further evaluated using qPCR comparing CACiv versus CD14+ monocytic cells. The CACiv transcriptome strongly related to tissue macrophages, and more specifically to regulatory M2c macrophages. The cytokine expression profile of CACiv was predominantly immune modulatory and resembled the cytokine expression of tumor-associated macrophages (TAM). Pathway analysis revealed previously unrecognized biological processes in CACiv, such as riboflavin metabolism and liver X receptor (LXR)/retinoid X receptor (RXR) and farnesoid X receptor (FXR)/retinoid X receptor (RXR) pathways. Analysis of endothelial-specific genes did not show evidence for endothelial transdifferentiation. Conclusions. CACiv are genotypically similar to regulatory M2c macrophages and lack signs of endothelial differentiation.
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Nakanishi, Tsuyoshi, Jun-ichi Nishikawa, Youhei Hiromori, Hideaki Yokoyama, Mihoko Koyanagi, Shinri Takasuga, Jun-ichi Ishizaki, et al. "Trialkyltin Compounds Bind Retinoid X Receptor to Alter Human Placental Endocrine Functions." Molecular Endocrinology 19, no. 10 (October 1, 2005): 2502–16. http://dx.doi.org/10.1210/me.2004-0397.
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Abstract Retinoid X receptor (RXR) is a nuclear receptor that plays important and multiple roles in mammalian development and homeostasis. We previously reported that, in human choriocarcinoma cells, tributyltin chloride and triphenyltin hydroxide, which are typical environmental contaminants and cause masculinization in female mollusks, are potent stimulators of human chorionic gonadotropin production and aromatase activity, which play key endocrine functions in maintaining pregnancy and fetal development. However, the molecular mechanism through which these compounds stimulate these endocrine functions remains unclear. Our current study shows that trialkyltin compounds, including tributyltin chloride and triphenyltin hydroxide, function as RXR agonists. Trialkyltins directly bind to the ligand-binding domain of RXR with high affinity and function as transcriptional activators. Unlike the natural RXR ligand, 9-cis-retinoic acid, the activity of trialkyltins is RXR specific and does not activate the retinoic acid receptor pathway. In addition, trialkyltins activate RXR to stimulate the expression of a luciferase reporter gene containing the human placental promoter I.1 sequence of aromatase, suggesting that trialkyltins stimulate human placental endocrine functions through RXR-dependent signaling pathways. Therefore, our results suggest that activation of RXR may be a novel mechanism by which trialkyltins alter human endocrine functions.
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Ruberte, E., V. Friederich, P. Chambon, and G. Morriss-Kay. "Retinoic acid receptors and cellular retinoid binding proteins. III. Their differential transcript distribution during mouse nervous system development." Development 118, no. 1 (May 1, 1993): 267–82. http://dx.doi.org/10.1242/dev.118.1.267.
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We have studied the transcript distribution of the retinoic acid receptors (RARs) and the cytoplasmic retinoid binding proteins during embryonic development of the mouse nervous system. Of the three retinoic acid receptors, only RAR-gamma was not expressed in developing neural structures. RAR-beta and RAR-alpha both showed rostral limits of expression in the medulla oblongata equivalent to their patterns of expression in the neuroepithelium of the early hindbrain neural tube. Within their expression domains in the spinal cord and brain, RAR-alpha was ubiquitously expressed, whereas RAR-beta transcripts showed very specific patterns of expression, suggesting that this receptor is involved in mediating retinoic acid-induced gene expression in relation to the development of specific neural structures or pathways. The cytoplasmic binding proteins, cellular retinoic acid binding proteins type I and II (CRABP I and CRABP II) and cellular retinol binding protein type I (CRBP I), were widely distributed in developing neural structures. Their differential spatiotemporal patterns of expression suggest that fine regional control of availability of retinoic acid (RA) to the nuclear receptors plays an important role in organization and differentiation of the nervous system. For instance, expression of CRABP I in the migrating cells that give rise to the olivary and pontine nuclei, which develop abnormally in conditions of retinoid excess, is consistent with observations from a variety of other systems indicating that CRABP I limits the access of RA to the nuclear receptors in normal physiological conditions. Similarly, expression of CRBP I in the choroid plexuses, which develop abnormally in conditions of vitamin A deficiency, is consistent with observations indicating that this binding protein mediates the synthesis of RA in tissues requiring high levels of RA for their normal developmental programme. RAR-beta and CRABP II, which are both RA-inducible, were coexpressed with CRBP I in the choroid plexus and in many other sites, perhaps reflecting the fact that all three genes are RA-inducible. The function of CRABP II is not well understood; its domains of expression showed overlaps with both CRABP I and CRBP I.
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Bland, R., R. L. Sammons, M. C. Sheppard, and G. R. Williams. "Thyroid hormone, vitamin D and retinoid receptor expression and signalling in primary cultures of rat osteoblastic and immortalised osteosarcoma cells." Journal of Endocrinology 154, no. 1 (July 1997): 63–74. http://dx.doi.org/10.1677/joe.0.1540063.
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Abstract 3,5,3′-Tri-iodothyronine (T3), 1α,25(OH)2-vitamin D3 (D3) and retinoids activate related nuclear receptors which interact by heterodimerisation to regulate gene expression. Actions of each hormone are discrete and may be specified by changes in the relative concentrations of their receptors (T3R, vitamin D receptor (VDR), retinoic acid receptor (RAR), retinoid X receptor (RXR)). T3, D3 and retinoids are essential for skeletal development and maintenance and we have previously shown complex interactions amongst their signalling pathways in osteosarcoma cells. In these studies we demonstrate that similar T3R, VDR, RAR and RXR proteins are co-expressed in both osteoblast lineage cell primary cultures and osteosarcoma cells by Western blotting. We investigated whether hormone interactions in bone result from changes in receptor stoichiometry. Cells were treated with combinations of T3, D3, 9-cis retinoic acid (9-cis RA) and all-trans retinoic acid (RA) that are known from previous studies to produce complex cell specific responses. No alteration in expression of any receptor protein was seen in response to any hormone combination in three phenotypically distinct osteosarcoma cell lines. Thus, in contrast to studies of overexpressed receptors in vitro, changes in the physiological concentrations of endogenous T3R, VDR, RAR and RXR do not specify discrete hormone actions in osteoblastic cells. Other unidentified factors are likely to modulate hormone action in these bone cells. Journal of Endocrinology (1997) 154, 63–74
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Xue, J. C., E. J. Schwarz, A. Chawla, and M. A. Lazar. "Distinct stages in adipogenesis revealed by retinoid inhibition of differentiation after induction of PPARgamma." Molecular and Cellular Biology 16, no. 4 (April 1996): 1567–75. http://dx.doi.org/10.1128/mcb.16.4.1567.
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Retinoic acid (RA) inhibits adipocyte differentiation of 3T3-L1 preadipocytes but is effective only early in adipogenesis. RA prevented induction of the adipogenic factors PPARgamma and C/EBPalpha. Using receptor-specific ligands, we determined that the effects of RA were mediated by liganded RA receptors (RARs) rather than retinoid X receptors. Preadipocytes expressed primarily RARalpha and RARgamma; during adipocyte differentiation, RARalpha gene expression was nearly constant, whereas RARgamma1 mRNA and protein levels dramatically decreased. Ectopic expression of RARgamma1 extended the period of effectiveness of RA by 24 to 48h; RARalpha expression had a similar effect, suggesting functional redundancy of RAR subtypes. Remarkably, RA inhibited differentiation when added after PPARgamma1 and PPARgamma2 proteins had already been expressed and resulted in the loss of PPARgamma proteins from cells. By 72 to 96 h after the induction of differentiation, RA failed to prevent differentiation of even ectopic-RAR-expressing cells. Thus, the unresponsiveness of 3T3-L1 preadipocytes to RA after the induction of differentiation is initially due to the reduction in cellular RAR concentration rather than to the induction of PPARgamma. At later times cells continue along the differentiation pathway in a manner which is RA and RAR independent.
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Bissonnette, R. P., T. Brunner, S. B. Lazarchik, N. J. Yoo, M. F. Boehm, D. R. Green, and R. A. Heyman. "9-cis retinoic acid inhibition of activation-induced apoptosis is mediated via regulation of fas ligand and requires retinoic acid receptor and retinoid X receptor activation." Molecular and Cellular Biology 15, no. 10 (October 1995): 5576–85. http://dx.doi.org/10.1128/mcb.15.10.5576.
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T-cell hybridomas, thymocytes, and T cells can be induced to undergo apoptotic cell death by activation through the T-cell receptor. This process requires macromolecular synthesis and thus gene expression, and it has been shown to be influenced by factors regulating transcription. Recently, activation, T-cell hybridomas rapidly express the Fas/CD95 receptor and its ligand, Fas ligand (FasL), which interact to transduce the death signal in the activated cell. Retinoids, the active metabolites of vitamin A, modulate expression of specific target genes by binding to two classes of intracellular receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). They are potent modulators of apoptosis in a number of experimental models, and they have been shown to inhibit activation-induced apoptosis in T-cell hybridomas and thymocytes. Particularly effective is the prototypic pan-agonist 9-cis retinoic acid (9-cis RA), which has high affinity for both RARs and RXRs. We report here that 9-cis RA inhibits T-cell receptor-mediated apoptosis in T-cell hybridomas by blocking the expression of Fas ligand following activation. This inhibition appears to be at the level of FasL mRNA, with the subsequent failure to express cell surface FasL. RAR-selective (TTNPB) or RXR-selective (LG100268) ligands alone were considerably less potent than RAR-RXR pan-agonists. However, the addition of both RAR- and RXR-selective ligands was as effective as the addition of 9-cis RA alone. The demonstrates that the inhibitory effect requires the ligand-mediated activation of both retinoid receptor signaling pathways.
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Aranda, Ana, and Angel Pascual. "Nuclear Hormone Receptors and Gene Expression." Physiological Reviews 81, no. 3 (July 1, 2001): 1269–304. http://dx.doi.org/10.1152/physrev.2001.81.3.1269.
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The nuclear hormone receptor superfamily includes receptors for thyroid and steroid hormones, retinoids and vitamin D, as well as different “orphan” receptors of unknown ligand. Ligands for some of these receptors have been recently identified, showing that products of lipid metabolism such as fatty acids, prostaglandins, or cholesterol derivatives can regulate gene expression by binding to nuclear receptors. Nuclear receptors act as ligand-inducible transcription factors by directly interacting as monomers, homodimers, or heterodimers with the retinoid X receptor with DNA response elements of target genes, as well as by “cross-talking” to other signaling pathways. The effects of nuclear receptors on transcription are mediated through recruitment of coregulators. A subset of receptors binds corepressor factors and actively represses target gene expression in the absence of ligand. Corepressors are found within multicomponent complexes that contain histone deacetylase activity. Deacetylation leads to chromatin compactation and transcriptional repression. Upon ligand binding, the receptors undergo a conformational change that allows the recruitment of multiple coactivator complexes. Some of these proteins are chromatin remodeling factors or possess histone acetylase activity, whereas others may interact directly with the basic transcriptional machinery. Recruitment of coactivator complexes to the target promoter causes chromatin decompactation and transcriptional activation. The characterization of corepressor and coactivator complexes, in concert with the identification of the specific interaction motifs in the receptors, has demonstrated the existence of a general molecular mechanism by which different receptors elicit their transcriptional responses in target genes.
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Anchan, Raymond M., Daniel P. Drake, Charles F. Haines, Elizabeth A. Gerwe, and Anthony-Samuel LaMantia. "Disruption of local retinoid-mediated gene expression accompanies abnormal development in the mammalian olfactory pathway." Journal of Comparative Neurology 379, no. 2 (March 10, 1997): 171–84. http://dx.doi.org/10.1002/(sici)1096-9861(19970310)379:2<171::aid-cne1>3.0.co;2-0.
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MacDonald, P. N., D. R. Dowd, S. Nakajima, M. A. Galligan, M. C. Reeder, C. A. Haussler, K. Ozato, and M. R. Haussler. "Retinoid X receptors stimulate and 9-cis retinoic acid inhibits 1,25-dihydroxyvitamin D3-activated expression of the rat osteocalcin gene." Molecular and Cellular Biology 13, no. 9 (September 1993): 5907–17. http://dx.doi.org/10.1128/mcb.13.9.5907.
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The vitamin D receptor (VDR) binds the vitamin D-responsive element (VDRE) as a heterodimer with an unidentified receptor auxiliary factor (RAF) present in mammalian cell nuclear extracts. VDR also interacts with the retinoid X receptors (RXRs), implying that RAF may be related to the RXRs. Here we demonstrate that highly purified HeLa cell RAF contained RXR beta immunoreactivity and that both activities copurified and precisely coeluted in high-resolution hydroxylapatite chromatography. Furthermore, an RXR beta-specific antibody disrupted VDR-RAF-VDRE complexes in mobility shift assays. These data strongly indicate that HeLa RAF is highly related to or is identical to RXR beta. Consequently, the effect of the 9-cis retinoic acid ligand for RXRs was examined in 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]-activated gene expression systems. Increasing concentrations of 9-cis retinoic acid (1 nM to 1 microM) markedly reduced 1,25(OH)2D3-dependent accumulation of osteocalcin mRNA in osteoblast-like ROS 17/2.8 cells. All-trans retinoic acid also interfered with vitamin D responsiveness, but it was consistently less potent than the 9-cis isomer. Transient transfection studies revealed that attenuation by 9-cis retinoic acid was at the transcriptional level and was mediated through interactions at the osteocalcin VDRE. Furthermore, overexpression of both RXR beta and RXR alpha augmented 1,25(OH)2D3 responsiveness in transient expression studies. Direct analysis of VDRE binding in mobility shift assays demonstrated that heteromeric interactions between VDR and RXR were enhanced by 1,25(OH)2D3 and were not affected appreciably by 9-cis retinoic acid, except that inhibition was observed at high retinoid concentrations. These data suggest a regulatory mechanism for osteocalcin gene expression that involves 1,25(OH)2D3-induced heterodimerization of VDR and unliganded RXR. 9-cis retinoic acid may attenuate 1,25(OH)2D3 responsiveness by diverting RXRs away from VDR-mediated transcription and towards other RXR-dependent transcriptional pathways.
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MacDonald, P. N., D. R. Dowd, S. Nakajima, M. A. Galligan, M. C. Reeder, C. A. Haussler, K. Ozato, and M. R. Haussler. "Retinoid X receptors stimulate and 9-cis retinoic acid inhibits 1,25-dihydroxyvitamin D3-activated expression of the rat osteocalcin gene." Molecular and Cellular Biology 13, no. 9 (September 1993): 5907–17. http://dx.doi.org/10.1128/mcb.13.9.5907-5917.1993.
Full textAbstract:
The vitamin D receptor (VDR) binds the vitamin D-responsive element (VDRE) as a heterodimer with an unidentified receptor auxiliary factor (RAF) present in mammalian cell nuclear extracts. VDR also interacts with the retinoid X receptors (RXRs), implying that RAF may be related to the RXRs. Here we demonstrate that highly purified HeLa cell RAF contained RXR beta immunoreactivity and that both activities copurified and precisely coeluted in high-resolution hydroxylapatite chromatography. Furthermore, an RXR beta-specific antibody disrupted VDR-RAF-VDRE complexes in mobility shift assays. These data strongly indicate that HeLa RAF is highly related to or is identical to RXR beta. Consequently, the effect of the 9-cis retinoic acid ligand for RXRs was examined in 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]-activated gene expression systems. Increasing concentrations of 9-cis retinoic acid (1 nM to 1 microM) markedly reduced 1,25(OH)2D3-dependent accumulation of osteocalcin mRNA in osteoblast-like ROS 17/2.8 cells. All-trans retinoic acid also interfered with vitamin D responsiveness, but it was consistently less potent than the 9-cis isomer. Transient transfection studies revealed that attenuation by 9-cis retinoic acid was at the transcriptional level and was mediated through interactions at the osteocalcin VDRE. Furthermore, overexpression of both RXR beta and RXR alpha augmented 1,25(OH)2D3 responsiveness in transient expression studies. Direct analysis of VDRE binding in mobility shift assays demonstrated that heteromeric interactions between VDR and RXR were enhanced by 1,25(OH)2D3 and were not affected appreciably by 9-cis retinoic acid, except that inhibition was observed at high retinoid concentrations. These data suggest a regulatory mechanism for osteocalcin gene expression that involves 1,25(OH)2D3-induced heterodimerization of VDR and unliganded RXR. 9-cis retinoic acid may attenuate 1,25(OH)2D3 responsiveness by diverting RXRs away from VDR-mediated transcription and towards other RXR-dependent transcriptional pathways.
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Boddicker, Rebecca L., Xueju Wang, Surendra Dasari, Grzegorz S. Nowakowski, Konstantinos N. Lazaridis, Eric D. Wieben, Marshall E. Kadin, and Andrew L. Feldman. "Retinoic Acid Receptor Alpha Expression Drives Cell-Cycle Progression and Is Associated with Increased Sensitivity to Retinoids in Peripheral T-Cell Lymphoma." Blood 128, no. 22 (December 2, 2016): 1749. http://dx.doi.org/10.1182/blood.v128.22.1749.1749.
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Abstract Background: Peripheral T-cell lymphomas (PTCLs) are aggressive non-Hodgkin lymphomas with marked clinical, pathological, and molecular heterogeneity. Outcomes following standard therapy generally are poor; however, few candidate therapeutic targets have been identified for precision medicine approaches. Retinoic acid receptor alpha (RARA) is a transcription factor that modulates cell growth and differentiation in response to natural or synthetic retinoids. Retinoids have been used successfully to treat acute promyelocytic leukemia and some cutaneous T-cell lymphomas (CTCLs). However, the function of RARA and the action of retinoids in PTCL have not been defined. Methods:Based on identification of a PTCL patient with a non-synonymous point mutation, RARA R394Q, identified in the Mayo Clinic Center for Individualized Medicine, we sought to characterize the role of RARA in PTCL cells. To investigate the role of wild-type and mutant RARA, we constructed expression vectors containing either wild-type RARA or RARA R394Q coding sequences, and also used siRNAs targeting RARA to study the role of native RARA expression. Cell lines derived from post-thymic T-cell malignancies were used for in vitro studies, including HuT78 and Mac-1 (both derived from circulating tumor cells from CTCL patients) and Karpas 299 (from an ALK-positive anaplastic large cell lymphoma). Following RARA overexpression or knockdown, we measured cell growth, cell cycle regulation, and sensitivity to synthetic retinoids. In addition, RNA sequencing and pathway analysis were performed to profile the transcriptomic response to retinoids in malignant T cells. Results:In two RARAlow cell lines, Karpas 299 and HuT78, overexpression of wild-type RARA or RARA R394Q significantly increased cell growth (p<0.001), with a greater increase observed from mutant versus wild-type RARA in Karpas 299 (136% of control versus 122%; p=0.04). Accordingly, knockdown of wild-type RARA in the RARAhigh cell line, Mac-1, resulted in a 22% inhibition of cell growth (p=0.0002). This inhibition specifically was associated with G1 cell cycle arrest (120% of control; p=0.004) and decreased protein expression of the G1-S-associated cyclin-dependent kinases, CDK2, CDK4, and CDK6. These kinases were up-regulated by overexpression of RARA in RARAlow HuT78 cells. The relatively RARA-specific retinoid, AM80 (tamibarotene), and the less specific retinoid, all-trans retinoic acid (ATRA), resulted in RARA protein degradation, cell growth inhibition that was both dose-dependent and proportional to baseline RARA expression, G1 arrest, and CDK protein up-regulation. Gene-set enrichment analysis (GSEA) of transcriptome data confirmed that genes down-regulated by AM80 were highly enriched for regulators of cell cycle and particularly G1-S transition. Finally, overexpressing RARA in RARAlow Karpas 299 and HuT78 cell lines significantly increased the ability of AM80 to inhibit CDK2/4/6 expression and cell growth (16% to 23% greater growth inhibition than control; p<0.05). Conclusions:RARA drives cyclin-dependent kinase expression and G1-S transition in malignant T cells, and promotes cell growth. These functions may be enhanced by specific RARA gene mutations. Synthetic retinoids inhibit these functions in a dose-dependent fashion, and are most effective in cells with high RARA expression. These data suggest RARA as a candidate therapeutic target in some PTCL patients. Disclosures Nowakowski: Celgene: Research Funding; Morphosys: Research Funding; Bayer: Consultancy, Research Funding.
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Glasow, Annegret, Angela Barrett, Rajeev Gupta, David Grimwade, Marieke von Lindern, Tariq Enver, and Arthur Zelent. "Expression of ATRA Inducible RARα2 Isoform Is Deregulated in AML." Blood 106, no. 11 (November 16, 2005): 1204. http://dx.doi.org/10.1182/blood.v106.11.1204.1204.
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Abstract Retinoids exert a variety of effects on both normal and malignant hematopoietic cells. To date, three different retinoic acid receptor (RAR) and retinoid X receptor (RXR) genes have been characterized, each encoding multiple N-terminal protein isoforms. RXRs serve as co-regulators for RARs, and many other nuclear receptors integrating different signalling pathways. All-trans-retinoic acid (ATRA) signaling pathway is of critical importance for optimal myelomonocytic differentiation and its disruption by translocations of the RARα gene leads to acute promyelocytic leukemia (APL). APL associated fusion oncoproteins, such as PML-RARα and PLZF-RARα, function through recruitment of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), thus promoting an inactive chromatin state and leading to repression of RARα target genes. Recently, we demonstrated that up-regulation of RARα2 expression by ATRA directly correlates with differentiation of APL and non-APL AML cells and that RARα2 transcription is silenced by DNA methylation in AML cell lines. Using primary AML samples as well as normal cord and peripheral blood derived cells representing different stages of myelomonocytic development we now show that expression of RARα2 increases with maturation of hematopietic cells. Expression of RARα1 on the other hand, which is transcribed from a distinct promoter, remains relatively constant throughout the different stages of myelomonocytic development. The levels of RARα1 expression in various primary AML cell types appear to be similar to those found in normal hematopietic cells. Consistent with data derived from AML cell lines, however, the RARα2 isoform is poorly expressed in all samples. Compared with CD34+/CD133+ or CD34+ progenitors, and more mature CD33+ myeloid cells, RARα2 is expressed at much lower levels in a variety of primary AML cells and its expression is not effectively induced by myelomonocytic growth factors and/or ATRA. Negatively acting epigenetic changes, such as DNA methylation, appear to be responsible for deregulated expression of RARα2 in AML cells, although their pattern and extent differs significantly between AML cell lines and primary AML samples. Taken together our data suggest that agents, which revert negatively acting epigenetic changes may restore expression of the RARα2 isoform in AML cells and render them more responsive to ATRA as well as other differentiation inducers.
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Han, Minjae, and Pyung Cheon Lee. "Microbial Production of Bioactive Retinoic Acid Using Metabolically Engineered Escherichia coli." Microorganisms 9, no. 7 (July 16, 2021): 1520. http://dx.doi.org/10.3390/microorganisms9071520.
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Microbial production of bioactive retinoids, including retinol and retinyl esters, has been successfully reported. Previously, there are no reports on the microbial biosynthesis of retinoic acid. Two genes (blhSR and raldhHS) encoding retinoic acid biosynthesis enzymes [β-carotene 15,15′-oxygenase (Blh) and retinaldehyde dehydrogenase2 (RALDH2)] were synthetically redesigned for modular expression. Co-expression of the blhSR and raldhHS genes on the plasmid system in an engineered β-carotene-producing Escherichia coli strain produced 0.59 ± 0.06 mg/L of retinoic acid after flask cultivation. Deletion of the ybbO gene encoding a promiscuous aldehyde reductase induced a 2.4-fold increase in retinoic acid production to 1.43 ± 0.06 mg/L. Engineering of the 5’-UTR sequence of the blhSR and raldhHS genes enhanced retinoic acid production to 3.46 ± 0.16 mg/L. A batch culture operated at 37 °C, pH 7.0, and 50% DO produced up to 8.20 ± 0.05 mg/L retinoic acid in a bioreactor. As the construction and culture of retinoic acid–producing bacterial strains are still at an early stage in the development, further optimization of the expression level of the retinoic acid pathway genes, protein engineering of Blh and RALDH2, and culture optimization should synergistically increase the current titer of retinoic acid in E. coli.
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Mey, Jörg. "Retinoic Acid as a Regulator of Cytokine Signaling after Nerve Injury." Zeitschrift für Naturforschung C 56, no. 3-4 (April 1, 2001): 163–76. http://dx.doi.org/10.1515/znc-2001-3-401.
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Abstract After an injury of the central nervous system it is of foremost clinical concern to prevent nerve cell degeneration and to develop strategies for the support of axonal regeneration. This requires an understanding of traumatic processes in the nervous system and their regulation by intercellular cytokine signaling. Although injury-induced temporal changes in gene expression of many cytokines have been described in this context, much less is known about their regulation. This review proposes a role of retinoic acid (RA) as transcriptional regulator in nerve regeneration. Four lines of evidence support this hypothesis: (1) In various cell culture systems retinoids were found to interact with most cytokine signals that mediate cellular interactions after nerve lesions in vivo. (2) Necessary components of the retinoid signaling pathway (aldehyde dehydrogenases, nuclear RA-receptors, cellular RA-binding proteins) are present in the adult nervous system, and glial cells produce RA in vitro. In addition, recent observations indicate that RA-synthesizing enzyme activity increases after nerve injury. (3) During development endogenous RA promotes glial and neuronal differentiation including the outgrowth of axons in the developing spinal cord, cerebellum, dorsal root ganglia and sympathetic ganglia. (4) Axonal regeneration of differentiated retinal ganglion cells and peripheral sensory neurons is enhanced by RA in vitro.
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Richards, Burt, Jon Karpilow, Christine Dunn, Isaac Peterson, Andrew Maxfield, Ludmilla Zharkikh, Majid Abedi, et al. "Genetic Selection for Modulators of a Retinoic-Acid-Responsive Reporter in Human Cells." Genetics 163, no. 3 (March 1, 2003): 1047–60. http://dx.doi.org/10.1093/genetics/163.3.1047.
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Abstract We used a genetic screening methodology, a human cell line bearing a retinoic-acid-responsive enhanced GFP reporter, and a flow sorter to recover dominant modulators of reporter expression. Four inducers and three suppressors that were fused to the C terminus of a protein scaffold for stability were isolated and their mechanisms of action studied. Mutagenesis experiments indicated that six of these dominant agents exerted their effects at the protein level. The single cDNA coding fragment that was isolated comprised the central 64-amino-acid section of human cyclophilin B, which contained its peptidyl-prolyl isomerase domain; this cyclophilin fragment repressed expression of the retinoic-acid-responsive reporter. The remaining clones encoded peptides shorter than 30 amino acids unrelated to known gene open reading frames. Genetic epistasis studies between the strongest inducer, R3, and a dominant-negative mutant of RARα suggest that the two factors function in the same pathway. Transcript microarray analyses suggest that R3 induced a subset of the retinoid-responsive genes in melanoma cells. Finally, yeast two-hybrid assays and co-immunoprecipitation studies of human cell extracts identified PAT1 as a protein that interacts with R3.
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Cheung, Cecilia Y., Debra F. Anderson, Marion Rouzaire, Loïc Blanchon, Vincent Sapin, and Robert A. Brace. "Retinoic Acid Pathway Regulation of Vascular Endothelial Growth Factor in Ovine Amnion." Reproductive Sciences 26, no. 10 (March 27, 2018): 1351–59. http://dx.doi.org/10.1177/1933719118765979.
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Vascular endothelial growth factor (VEGF) has been proposed as an important regulator of amniotic fluid absorption across the amnion into the fetal vasculature on the surface of the placenta. However, the activators of VEGF expression and action in the amnion have not been identified. Using the pregnant sheep model, we aimed to investigate the presence of the retinoic acid (RA) pathway in ovine amnion and to determine its effect on VEGF expression. Further, we explored relationships between RA receptors and VEGF and tested the hypothesis that RA modulates intramembranous absorption (IMA) through induction of amnion VEGF in sheep fetuses subjected to altered IMA rates. Our study showed that RA receptor isoforms were expressed in sheep amnion, and RA response elements (RAREs) were identified in ovine RARβ and VEGF gene promoters. In ovine amnion cells, RA treatment upregulated RARβ messenger RNA (mRNA) and increased VEGF transcript levels. In sheep fetuses, increases in IMA rate was associated with elevated VEGF mRNA levels in the amnion but not in the chorion. Further, RARβ mRNA was positively correlated with VEGF mRNA levels in the amnion and not chorion. We conclude that an RA pathway is present in ovine fetal membranes and that RA is capable of inducing VEGF. The finding of a positive relationship between amnion VEGF and RARβ during altered IMA rate suggests that the retinoid pathway may play a role through VEGF in regulating intramembranous transport across the amnion.
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Niu, Haixia, Gayla Hadwiger, Hideji Fujiwara, and John S. Welch. "Pathways of Retinoid Synthesis in Mouse Bone Marrow-Derived Macrophages and Hematopoietic Progenitors." Blood 126, no. 23 (December 3, 2015): 1009. http://dx.doi.org/10.1182/blood.v126.23.1009.1009.
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Abstract Introduction: Retinoid receptors are nuclear hormone receptors which are dynamically regulated during terminal myeloid maturation. Retinoic acid receptor α (RARA) is the target of at least ten fusion proteins that lead to acute promyelocytic leukemia (APL). All trans-retinoic acid (ATRA) has been thought to be the principle natural ligand for RARs and it has been used for the treatment of patients with APL. However, the enzymatic pathways that regulate natural retinoids metabolism in hematopoietic cells have not been well defined. ATRA is synthesized from vitamin A through two sequential steps. Vitamin A is oxidized by an alcohol dehydrogenase to yield retinal, which is then irreversibly oxidized by an aldehyde dehydrogenase (ALDH) to generate retinoic acid (RA). At least 19 different human ALDHs have been identified. Among them, ALDH1A1, ALDH1A2 and ALDH1A3 have been shown to oxidize all trans-retinal to ATRA with high affinity, which can be inhibited by diethylaminobenzaldehyde (DEAB). Whether other ALDHs participate in RA metabolism is unknown. Our study identified two distinct retinoid metabolism pathways that are active in bone marrow (BM) progenitors and in macrophages (Mφ). Methods: Gal4-UAS reporter system was used to detect natural RARA ligands in mouse primary hematopoietic cells. We transduced UAS-GFP mouse BM cells with retrovirus that expresses a fusion protein containing the DNA binding domain of Gal4 (which recognizes the UAS promoter) and the ligand binding domain of RARA. An IRES mCherry cassette was included for normalization purposes. Transduced cells were cultured in vitro, or transplanted into lethally irradiated recipient mice. Cells with intracellular RARA ligands activate GFP expression. GFP and mCherry expression were evaluated by flow cytometry. Real-time PCR and Affymetrix array were used to quantify ALDH expression. We identified RARA ligands by mass spectrometry (MS). Results: In vitro, we found that both mouse BM Kit+ cells (Kit+ progenitors) and BM-derived macrophages (BMMφ) could synthesize active RARA ligands via different pathways, but only when the cell culture media was supplemented with vitamin A. Kit+ progenitors utilize DEAB-sensitive ALDH pathways, whereas BMMφ use DEAB-insensitive pathways. By real-time PCR we found Kit+ progenitors have high expression of Aldh1a1, Aldh1a2 and Aldh1a3, whereas BMMφ have no detectable expression of these enzymes. We compared gene expression in Kit+ progenitors and BMMφ by Affymetrix profiling and found that Aldh3b1 was overexpressed in BMMφ. Ectopic expression of Aldh3b1 in 293T cells resulted activation of the same GFP reporter, which could be abrogated by two different antagonist, Ro41-5253 and BMS493, suggesting that Aldh3b1 generated an RARA specific ligand, which we subsequently identified as ATRA via MS. Reciprocally, we found that siRNA knock down of Aldh3b1 in BMMφ reduced the transactivation of the RARA-dependent GFP reporter. The X-RARA fusions have been proposed to act via dominant-negative mechanisms, decreasing retinoid-dependent transcription and myeloid maturation. Surprisingly, in vivo, only rare GFPdim cells were observed in BM cells and no GFP positive cells in peritoneal Mφ of UAS-GFP/Gal4-RARA transplant mice. As positive control, we treated mice with ATRA and observed a dose-dependent GFP increase in both cell types, suggesting that the in vivo reporter can respond to ATRA, but ATRA is not synthesized during adult hematopoiesis, and that dominant-negative inhibition of ATRA-dependent transcription may not be the predominant pathogenic effect of the X-RARA fusion oncoproteins. Conclusion: We have found that at least two distinct enzymatic pathways may be utilized in primary hematopoietic cells to synthesize active RARA ligands from vitamin A. Mouse BM Kit+ progenitors predominantly employ a set of DEAB-sensitive enzymes (Aldh1a1, Aldh1a2 and Aldh1a3), whereas Mφ utilize DEAB-insensitive pathways. We identified Aldh3b1 as a likely candidate and shown that it is capable of ATRA synthesis in vitro. Although these enzymes are expressed in primary BM cells, we found that this does not result in active intracellular RARA ligands in monocytes or Mφ in vivo, suggesting that the rate-limiting step in retinoid synthesis in vivo is likely to involve additional enzymes required for intracellular transport of protein-bound, serum-available vitamin A. Disclosures No relevant conflicts of interest to declare.
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Viswakarma, Navin, Yuzhi Jia, Liang Bai, Aurore Vluggens, Jayme Borensztajn, Jianming Xu, and Janardan K. Reddy. "Coactivators in PPAR-Regulated Gene Expression." PPAR Research 2010 (2010): 1–21. http://dx.doi.org/10.1155/2010/250126.
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Peroxisome proliferator-activated receptor (PPAR)α,β(also known asδ), andγfunction as sensors for fatty acids and fatty acid derivatives and control important metabolic pathways involved in the maintenance of energy balance. PPARs also regulate other diverse biological processes such as development, differentiation, inflammation, and neoplasia. In the nucleus, PPARs exist as heterodimers with retinoid X receptor-αbound to DNA with corepressor molecules. Upon ligand activation, PPARs undergo conformational changes that facilitate the dissociation of corepressor molecules and invoke a spatiotemporally orchestrated recruitment of transcription cofactors including coactivators and coactivator-associated proteins. While a given nuclear receptor regulates the expression of a prescribed set of target genes, coactivators are likely to influence the functioning of many regulators and thus affect the transcription of many genes. Evidence suggests that some of the coactivators such as PPAR-binding protein (PBP/PPARBP)/thyroid hormone receptor-associated protein 220 (TRAP220)/mediator complex subunit 1 (MED1) may exert a broader influence on the functions of several nuclear receptors and their target genes. Investigations into the role of coactivators in the function of PPARs should strengthen our understanding of the complexities of metabolic diseases associated with energy metabolism.
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Nones, Katia, Yvonne E. M. Dommels, Sheridan Martell, Christine Butts, Warren C. McNabb, Zaneta A. Park, Shuotun Zhu, Duncan Hedderley, Matthew P. G. Barnett, and Nicole C. Roy. "The effects of dietary curcumin and rutin on colonic inflammation and gene expression in multidrug resistance gene-deficient (mdr1a−/−) mice, a model of inflammatory bowel diseases." British Journal of Nutrition 101, no. 2 (September 2, 2008): 169–81. http://dx.doi.org/10.1017/s0007114508009847.
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Damage of the intestinal epithelial barrier by xenobiotics or reactive oxygen species and a dysregulated immune response are both factors involved in the pathogenesis of inflammatory bowel diseases (IBD). Curcumin and rutin are polyphenolic compounds known to have antioxidant and anti-inflammatory activities, but their mechanism(s) of action are yet to be fully elucidated. Multidrug resistance gene-deficient (mdr1a− / − ) mice spontaneously develop intestinal inflammation, predominantly in the colon, with pathology similar to IBD, so this mouse model is relevant for studying diet–gene interactions and potential effects of foods on remission or development of IBD. The present study tested whether the addition of curcumin or rutin to the diet would alleviate colonic inflammation in mdr1a− / − mice. Using whole-genome microarrays, the effect of dietary curcumin on gene expression in colon tissue was also investigated. Twelve mice were randomly assigned to each of three diets (control (AIN-76A), control +0·2 % curcumin or control +0·1 % rutin) and monitored from the age of 7 to 24 weeks. Curcumin, but not rutin, significantly reduced histological signs of colonic inflammation in mdr1a− / − mice. Microarray and pathway analyses suggested that the effect of dietary curcumin on colon inflammation could be via an up-regulation of xenobiotic metabolism and a down-regulation of pro-inflammatory pathways, probably mediated by pregnane X receptor (Pxr) and peroxisome proliferator-activated receptor α (Ppara) activation of retinoid X receptor (Rxr). These results indicate the potential of global gene expression and pathway analyses to study and better understand the effect of foods in modulating colonic inflammation.
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Rottman, J. N., R. L. Widom, B. Nadal-Ginard, V. Mahdavi, and S. K. Karathanasis. "A retinoic acid-responsive element in the apolipoprotein AI gene distinguishes between two different retinoic acid response pathways." Molecular and Cellular Biology 11, no. 7 (July 1991): 3814–20. http://dx.doi.org/10.1128/mcb.11.7.3814.
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The gene coding for apolipoprotein AI, a plasma protein involved in the transport of cholesterol and other lipids in the plasma, is expressed predominantly in liver and intestine. Previous work in our laboratory has shown that hepatocyte-specific expression is determined by synergistic interactions between transcription factors bound to three separate sites, sites A (-214 to -192), B (-169 to -146), and C (-134 to -119), within a powerful liver-specific enhancer located in the region -222 to -110 nucleotides upstream of the apolipoprotein AI gene transcription start site (+1). In this study, it was found that site A is a highly selective retinoic acid-responsive element (RARE) that responds preferentially to the recently identified retinoic acid receptor RXR alpha over the previously characterized retinoic acid receptors RAR alpha and RAR beta. Control experiments indicated that a RARE in the regulatory region of the laminin B1 gene responds preferentially to RAR alpha and RAR beta over RXR alpha, while a previously described palindromic thyroid hormone-responsive element responds similarly to all three of these receptors. Gel retardation experiments showed that the activity of these RAREs is concordant with receptor binding. These results indicate that different RAREs may play a fundamental role in defining distinctive retinoic acid cellular response pathways and suggest that retinoic acid response pathways mediated by RXR alpha play an important role in cholesterol and retinoid transport and metabolism.
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Rottman, J. N., R. L. Widom, B. Nadal-Ginard, V. Mahdavi, and S. K. Karathanasis. "A retinoic acid-responsive element in the apolipoprotein AI gene distinguishes between two different retinoic acid response pathways." Molecular and Cellular Biology 11, no. 7 (July 1991): 3814–20. http://dx.doi.org/10.1128/mcb.11.7.3814-3820.1991.
Full textAbstract:
The gene coding for apolipoprotein AI, a plasma protein involved in the transport of cholesterol and other lipids in the plasma, is expressed predominantly in liver and intestine. Previous work in our laboratory has shown that hepatocyte-specific expression is determined by synergistic interactions between transcription factors bound to three separate sites, sites A (-214 to -192), B (-169 to -146), and C (-134 to -119), within a powerful liver-specific enhancer located in the region -222 to -110 nucleotides upstream of the apolipoprotein AI gene transcription start site (+1). In this study, it was found that site A is a highly selective retinoic acid-responsive element (RARE) that responds preferentially to the recently identified retinoic acid receptor RXR alpha over the previously characterized retinoic acid receptors RAR alpha and RAR beta. Control experiments indicated that a RARE in the regulatory region of the laminin B1 gene responds preferentially to RAR alpha and RAR beta over RXR alpha, while a previously described palindromic thyroid hormone-responsive element responds similarly to all three of these receptors. Gel retardation experiments showed that the activity of these RAREs is concordant with receptor binding. These results indicate that different RAREs may play a fundamental role in defining distinctive retinoic acid cellular response pathways and suggest that retinoic acid response pathways mediated by RXR alpha play an important role in cholesterol and retinoid transport and metabolism.
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Rodriguez, A., L. J. Royo, F. Goyache, C. Diez, E. Moran, A. Salas, and E. Gomez. "249BOVINE GRANULOSA CELLS MRNA EXPRESSION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-± AND THE PROTO-ONCOGENE C-FOS." Reproduction, Fertility and Development 16, no. 2 (2004): 245. http://dx.doi.org/10.1071/rdv16n1ab249.
Full textAbstract:
PPARα and c-Fos are involved in regulation of gene expression and are known to be dependent on retinoic acid (RA), which in turn influences oocyte growth and developmental competence (Duque et al., 2002 Hum. Reprod. 17, 2706–2714; Hidalgo et al., 2003. Reproduction 125, 409–416), probably acting in part through granulosa cells. Peroxisome proliferator-activated receptor-α (PPARα) heterodimerizes with the retinoid receptor X (RXR), while c-Jun/c-Fos heterodimerizes with liganded retinoic acid receptors (RARs), then preventing formation of transcription factor activator protein 1 (AP-1) complexes capable of DNA binding. Cellular retinoic acid binding protein (CRABP) limits RA excess and regulates the transcriptional potential of RA;; CRABPII has been detected in rat granulosa cells from mature follicles and luteal cells. The aim of this study was to investigate PPARα, c-Fos and CRABPII mRNA expression in bovine granulosa cells. In parallel, other genes whose expression can be influenced by RA were analyzed: luteinizing hormone receptor (LHr), follicle stimulating hormone receptor (FSHr), aromatase and growth hormone (GH). Ovaries were collected at a local abattoir and kept in saline at 30–35°C. Granulosa cells were obtained by aspirating 2- to 7-mm antral follicle contents, pelleted at 700g for 4min and resuspended in RNA-later (Ambion®). Total RNA was isolated with a NucleoSpin® RNAII kit (Macherey-Nagel), and mRNA was reverse transcribed into single-stranded cDNA using a 1st Strand cDNA Synthesis Kit for RT-PCR (AMV) (Roche). A PCR standard method was made using 1μL of the cDNA as a template. All PCR primer couples were designed on the basis of the bovine sequence, but c-Fos and CRABPII primers were designed based on the human-murine sequences. Primers within the couple were located in different exons to distinguish DNA from RNA amplification. CRABPII was further investigated in bovine whole ovary, corpus luteum (CL) and liver, in a search for positive controls. Bovine β-actin, 18S and 28S were examined in each sample as positive controls for RNA isolation and cDNA synthesis efficiency. TenμL of product were loaded into an agarose 2% gel in TBE buffer containing ethidium bromide, and were separated by horizontal electrophoresis. Gels were visualized with ultraviolet light and photographed using a digital camera. Gene expression in granulosa was demonstrated for PPARα, c-Fos, LHr, FSHr, aromatase, GH and controls (β-actin, 18S and 28S) but CRABPII gene did not express in granulosa cells, whole ovary, CL or liver under our experimental conditions. While lacking CRABPII expression remains intriguing, the expressed genes support a role of retinoid pathway within granulosa cells under both in vivo and in vitro conditions, because granulosa cells used in the present experiments were derived from follicles providing oocytes for IVM-IVF. Grant support: Spanish Ministry of Science and Technology (AGL-2002-01175).
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Kugita, Masanori, Kazuhiro Nishii, Miwa Morita, Daisuke Yoshihara, Hiroe Kowa-Sugiyama, Kouji Yamada, Tamio Yamaguchi, et al. "Global gene expression profiling in early-stage polycystic kidney disease in the Han:SPRD Cy rat identifies a role for RXR signaling." American Journal of Physiology-Renal Physiology 300, no. 1 (January 2011): F177—F188. http://dx.doi.org/10.1152/ajprenal.00470.2010.
Full textAbstract:
Han:SPRD Cy is a spontaneous rat model of polycystic kidney disease (PKD) caused by a missense mutation in Pkdr1. Cystogenesis in this model is not clearly understood. In the current study, we performed global gene expression profiling in early-stage PKD cyst development in Cy/Cy kidneys and normal (+/+) kidneys at 3 and 7 days of postnatal age. Expression profiles were determined by microarray analysis, followed by validation with real-time RT-PCR. Genes were selected with over 1.5-fold expression changes compared with age-matched +/+ kidneys for canonical pathway analysis. We found nine pathways in common between 3- and 7-day Cy/Cy kidneys. Three significantly changed pathways were designated “Vitamin D Receptor (VDR)/Retinoid X Receptor (RXR) Activation,” “LPS/IL-1-Mediated Inhibition of RXR Function,” and “Liver X Receptor (LXR)/RXR Activation.” These results suggest that RXR-mediated signaling is significantly altered in developing kidneys with mutated Pkdr1. In gene ontology analysis, the functions of these RXR-related genes were found to be involved in regulating cell proliferation and organ morphogenesis. With real-time RT-PCR analysis, the upregulation of Ptx2, Alox15b, OSP, and PCNA, major markers of cell proliferation associated with the RXR pathway, were confirmed in 3- and 7-day Cy/Cy kidneys compared with 3-day +/+ kidneys. The increased RXR protein was observed in both the nucleus and cytoplasm of cystic epithelial cells in early-stage Cy/Cy kidneys, and the RXR-positive cells were strongly positive for PCNA staining. Taken together, cell proliferation and organ morphogenesis signals transduced by RXR-mediated pathways may have important roles for cystogenesis in early-stage PKD in this Pkdr1-mutated Cy rat.