DOCSLIB.ORG

Ligand-Activated Retinoic Acid Receptor Inhibits AP-1 Transactivation by Disrupting C-Jun/C-Fos Dimerization

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Ligand-Activated Retinoic Acid Receptor Inhibits AP-1 Transactivation by Disrupting C-Jun/C-Fos Dimerization Ligand-Activated Retinoic Acid Receptor Inhibits AP-1 Transactivation by Disrupting c-Jun/c-Fos Dimerization Xiao-Feng Zhou, Xi-Qiang Shen, and Lirim Shemshedini Downloaded from https://academic.oup.com/mend/article/13/2/276/2741651 by guest on 27 September 2021 Department of Biology University of Toledo Toledo, Ohio 43606 In the presence of retinoic acid (RA), the retinoid volved in epithelial differentiation (2), has a central role receptors, retinoic acid receptor (RAR) and retinoid as a tissue-specific morphogen during embryogenesis X receptor (RXR), are able to up-regulate transcrip- (3), and represses malignant transformation of epithe- tion directly by binding to RA-responsive elements lial cells both in vitro (4) and in vivo (5). These diverse on the promoters of responsive genes. Liganded and pleiotropic effects of RA are mediated through the RARs and RXRs are also capable of down-regulat- binding of RA to a family of nuclear receptors, which, ing transcription, but, by contrast, this is an indi- together with the receptors for steroid and thyroid rect effect, mediated by the interaction of these hormones and vitamin D, form the nuclear receptor nuclear receptors not with DNA but the transcrip- superfamily (reviewed in Refs. 6–10). Nuclear recep- tion factor activating protein-1 (AP-1). AP-1 is a tors comprise the largest family of transcription fac- dimeric complex of the protooncoproteins c-Jun tors, which, upon binding of their cognate ligands, and c-Fos and directly regulates transcription of modulate transcription initiated from promoters of tar- genes important for cellular growth. Previous in get genes by interacting with specific cis-acting, DNA vitro results have suggested that RARs can block response elements. AP-1 DNA binding. Using a mammalian two-hybrid In contrast to this positive effect of nuclear recep- system, we report here that human RARa (hRARa) tors on transcription, which requires receptor-DNA in- can disrupt in a RA-dependent manner the homo- teractions, the retinoid receptors and other nuclear and heterodimerization properties of c-Jun and c- receptors can negatively affect gene expression with- Fos. This inhibition of dimerization is cell specific, out binding to DNA, via their ability to functionally occurring only in those cells that exhibit RA- interact with the transcription factor AP-1 (activating induced repression of AP-1 transcriptional activity. protein-1) (reviewed in Refs. 11–14). AP-1 consists of Furthermore, this mechanism appears to be spe- homodimers and heterodimers of Jun (c-Jun, v-Jun, cific for the RARs, since another potent inhibitor of JunB, and JunD), Fos (c-Fos, v-Fos, FosB, Fra1, and AP-1 activity, the glucocorticoid receptor, does not Fra2), or activating transcription factor (ATF2, ATF3/ affect AP-1 dimerization. Our data argue for a novel LRF1, B-ATF) bZIP (basic region leucine zipper) pro- mechanism by which RARs can repress AP-1 DNA teins (15–17). The transcription of the c-jun and c-fos binding, in which liganded RARs are able to inter- genes, encoding the major components of AP-1, is fere with c-Jun/c-Jun homodimerization and rapidly induced upon stimulation of cellular prolifera- c-Jun/c-Fos heterodimerization and, in this way, tion (37, 38). Like nuclear receptors, AP-1 activates may prevent the formation of AP-1 complexes ca- transcription of target genes by binding to specific pable of DNA binding. (Molecular Endocrinology promoter elements, called TREs (TPA-responsive ele- 13: 276–285, 1999) ments) (17, 18). TPA (12-O-tetra-decanoyl-phorbol- 13-acetate) is a tumor promoter that induces the ex- pression of the c-fos and c-jun genes (19, 20) and INTRODUCTION thereby indirectly stimulates the expression of AP-1 target genes. Retinoic acid (RA), the most biologically active natural Both positive and negative regulatory interactions metabolite of vitamin A (retinol), exerts profound ef- between nuclear receptors and c-Jun/c-Fos have fects on vertebrate development, cellular differentia- been reported (reviewed in Refs. 11–14). The first re- tion, and homeostasis (reviewed in Ref. 1). RA is in- sults showed an inhibition of glucocorticoid receptor (GR)-induced transcription by either c-Fos or c-Jun 0888-8809/99/$3.00/0 (21–24). We (25) and others (26–31) have shown that Molecular Endocrinology Copyright © 1999 by The Endocrine Society this type of interference is not restricted to the GR, but 276 RAR Blocks c-Jun/c-Fos Dimerization 277 seems to be a common characteristic of nuclear re- Using a mammalian two-hybrid system, we provide ceptors, including the receptors for the hormones pro- evidence here that RAR, but not GR, is able to disrupt gesterone (PR), estrogen (ER), androgen (AR), and thy- in vivo c-Jun/c-Fos dimerization in a ligand-dependent roid (TRs), and the RA (RARs, RXRs). Conversely, the manner. This effect is not only receptor specific, but activation of the collagenase and stromelysin genes by also cell specific, paralleling what has been reported AP-1 is repressed in a ligand-dependent manner by previously with RA-induced inhibition of AP-1 tran- several receptors, including GR (21–24), PR (25), AR scriptional activity (27). Our results suggest that c-Jun/ (25), ER (25), TR (28), and RARs/RXRs (26, 27, 29). By c-Fos dimerization may be a third target of nuclear contrast, coexpression of c-Jun, c-Fos, and ER receptor-mediated repression of AP-1 that may be causes synergistic activation of the ovalbumin gene specific for the transrepression activity of RARs and (32). GR has been shown to potentiate c-Jun-acti- may partially explain the receptor- and cell-specific Downloaded from https://academic.oup.com/mend/article/13/2/276/2741651 by guest on 27 September 2021 vated transcription from the proliferin- regulatory ele- nature of this repression. ment (33). Similarly, transfected c-Jun enhances AR- induced transactivation, but it does so independently of promoter or cell type specificity (25, 34, 35). RESULTS In contrast to the interaction between AP-1 and AR, PR, or GR, which is nonmutual and can be either RA-Bound human RARa (hRARa) Inhibits AP-1 negative or positive (25, 32, 33), the interaction be- Activity in a Cell-Specific Manner tween AP-1 and the retinoid receptors is mutual and solely inhibitory. c-Jun and c-Fos, either individually or The interaction between nuclear receptors and AP-1 together, have been shown to repress the transcrip- has been shown previously to be dependent on cell tional activity of RAR and/or RXR (27). Conversely, type (Refs. 25 and 27; reviewed in Ref. 11). To test for both RAR/RXR heterodimers or homodimers of either cell specificity in RARs’ ability to inhibit AP-1 transcrip- can inhibit AP-1 transactivation of several AP-1- tional activity, cells were transiently transfected with a responsive promoters (27, 29). Indeed, the RAR/RXR expression plasmids for c-Jun and hRAR and the antagonism of AP-1 has been directly implicated in the AP-1-inducible reporter TRE-tk-CAT (34). In keeping a regulation of collagenase (27, 29) and stromelysin (26), with previously published data (27), hRAR inhibited in two genes that play key roles in tumor potential and a ligand- and dose-dependent manner exogenous c- invasiveness. Jun activity in HeLa cells (Fig. 1A), but not in Cos cells While the molecular bases of these diverse regula- (Fig. 1B). The same difference in activity was observed tory interactions between nuclear receptors and AP-1 on endogenous AP-1 activity (data not shown). are not known, recent studies provide several attrac- Mammalian Two-Hybrid System Can Be Used to tive models. Based on the demonstration that CREB- Measure c-Jun/c-Fos Dimerization in Vivo binding protein (CBP) and the related p300 can act as transcriptional coactivators for both nuclear receptors The yeast two-hybrid system has been used previ- (36–38) and AP-1 (39, 40), it has been proposed that ously to measure in vivo protein-protein interactions the nuclear receptor-AP-1 antagonism depends on (45). In the current study, we have used a similar competition for limiting amounts of these two coacti- system to measure c-Jun/c-Fos heterodimerization vator proteins (36). While this model may explain some and c-Jun/c-Jun homodimerization in cultured mam- of the observations made, it is not able to explain all of malian cells. In our system, two fusion proteins are the cell, promoter, and receptor specificity that has expressed, one containing the GAL4 DNA-binding do- been observed in the nuclear receptor-AP-1 interac- main (DBD) fused to either full-length c-Jun or only its tions (25). More recently, it has been suggested that bZIP region and the other containing the VP16 trans- GR, RARs, and TRs can block AP-1 activity by inhib- activation domain fused to either full-length c-Fos or iting the activity of Jun amino-terminal kinase (JNK) only its bZIP region (Fig. 2A). HeLa cells were trans- (41), which enhances c-Jun transcriptional activity by fected with expression plasmids for these different phosphorylating Ser63/73 (42, 43). However, this fusion proteins, and dimerization was monitored with model also is unable to account for the diverse nature the GAL4-inducible reporter 17M-tk-CAT. While GAL- of the interactions between nuclear receptors and cJun had a weak activity and VP16-cFos had no mea- AP-1. Others have argued, based on in vitro results, surable activity, these two fusion proteins together that AP-1 and receptors mutually inhibit each other’s resulted in a 14-fold stimulation in transcription (Fig. DNA-binding ability (21, 24, 33).
Load more

Recommended publications
  • Retinoic Acid Signaling and Neuronal Differentiation
    Cell. Mol. Life Sci. (2015) 72:1559–1576 DOI 10.1007/s00018-014-1815-9 Cellular and Molecular Life Sciences REVIEW Retinoic acid signaling and neuronal differentiation Amanda Janesick • Stephanie Cherie Wu • Bruce Blumberg Received: 23 October 2014 / Revised: 15 December 2014 / Accepted: 19 December 2014 / Published online: 6 January 2015 Ó Springer Basel 2015 Abstract The identification of neurological symptoms cell cycle exit downstream of RA will be critical for our caused by vitamin A deficiency pointed to a critical, early understanding of how to target tumor differentiation. developmental role of vitamin A and its metabolite, reti- Overall, elucidating the molecular details of RAR-regu- noic acid (RA). The ability of RA to induce post-mitotic, lated neurogenesis will be decisive for developing and neural phenotypes in various stem cells, in vitro, served as understanding neural proliferation–differentiation switches early evidence that RA is involved in the switch between throughout development. proliferation and differentiation. In vivo studies have expanded this ‘‘opposing signal’’ model, and the number of Keywords Neurogenesis Á Retinoic acid receptor Á primary neurons an embryo develops is now known to Proliferation-differentiation switch depend critically on the levels and spatial distribution of RA. The proneural and neurogenic transcription factors that control the exit of neural progenitors from the cell Introduction cycle and allow primary neurons to develop are partly elucidated, but the downstream effectors of RA receptor The role of retinoic acid (RA) in neurogenesis has been (RAR) signaling (many of which are putative cell cycle known indirectly for as long as haliver (halibut) and cod liver regulators) remain largely unidentified.
    [Show full text]
  • Signaling by Retinoic Acid in Embryonic and Adult Hematopoiesis
    J. Dev. Biol. 2014, 2, 18-33; doi:10.3390/jdb2010018 OPEN ACCESS Journal of Developmental Biology ISSN 2221-3759 www.mdpi.com/journal/jdb/ Review Signaling by Retinoic Acid in Embryonic and Adult Hematopoiesis Elena Cano †, Laura Ariza †, Ramón Muñoz-Chápuli and Rita Carmona * Department of Animal Biology, Faculty of Science, University of Málaga, E29071 Málaga, Spain; E-Mails: [email protected] (E.C.); [email protected] (L.A.); [email protected] (R.M.-C.) † These authors contributed equally to this paper. * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +34-952-134-135; Fax: +34-952-131-668. Received: 3 February 2014; in revised form: 5 March 2014 / Accepted: 6 March 2014 / Published: 17 March 2014 Abstract: Embryonic and adult hematopoiesis are both finely regulated by a number of signaling mechanisms. In the mammalian embryo, short-term and long-term hematopoietic stem cells (HSC) arise from a subset of endothelial cells which constitute the hemogenic endothelium. These HSC expand and give rise to all the lineages of blood cells in the fetal liver, first, and in the bone marrow from the end of the gestation and throughout the adult life. The retinoic acid (RA) signaling system, acting through the family of nuclear retinoic acid receptors (RARs and RXRs), is involved in multiple steps of the hematopoietic development, and also in the regulation of the differentiation of some myeloid lineages in adults. In humans, the importance of this RA-mediated control is dramatically illustrated by the pathogeny of acute promyelocytic leukemia, a disease produced by a chromosomal rearrangement fusing the RAR gene with other genes.
    [Show full text]
  • Pathway Development Via Retinoid X Receptor Vitamin a Enhances In
    Vitamin A Enhances in Vitro Th2 Development Via Retinoid X Receptor Pathway This information is current as Charles B. Stephensen, Reuven Rasooly, Xiaowen Jiang, of September 24, 2021. Michael A. Ceddia, Casey T. Weaver, Roshantha A. S. Chandraratna and R. Patterson Bucy J Immunol 2002; 168:4495-4503; ; doi: 10.4049/jimmunol.168.9.4495 http://www.jimmunol.org/content/168/9/4495 Downloaded from References This article cites 40 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/168/9/4495.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 24, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2002 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Vitamin A Enhances in Vitro Th2 Development Via Retinoid X Receptor Pathway1 Charles B. Stephensen,2* Reuven Rasooly,* Xiaowen Jiang,* Michael A. Ceddia,3* Casey T. Weaver,† Roshantha A. S. Chandraratna,‡ and R. Patterson Bucy† Vitamin A deficiency diminishes Th2-mediated Ab responses, and high-level dietary vitamin A or treatment with the vitamin A metabolite retinoic acid (RA) enhances such responses.
    [Show full text]
  • Peroxisome Proliferator-Activated Receptor ; Is Highly Expressed In
    Imaging, Diagnosis, Prognosis Peroxisome Proliferator-Activated Receptor ; Is Highly Expressed in Pancreatic Cancer and Is Associated With Shorter Overall Survival Times Glen Kristiansen,1Juliane Jacob,1Ann-Christin Buckendahl,1Robert Gru« tzmann,3 Ingo Alldinger,3 Bence Sipos,4 Gu« nter Klo« ppel,4 Marcus Bahra,2 Jan M. Langrehr,2 Peter Neuhaus,2 Manfred Dietel,1and Christian Pilarsky3 Abstract Purpose: Peroxisome proliferator-activated receptor g (PPARg) is a ligand-activated transcrip- tion factor that has been implicated in carcinogenesis and progression of various solid tumors, including pancreatic carcinoma.We aimed to clarify the expression patterns of PPARg in pancre- atic ductal carcinomas and to correlate these to clinicopathologic variables, including patient survival. Experimental Design: Array-based expression profiling of 19 microdissected carcinomas and 14 normal ductal epithelia was conducted. Additionally,Western blots of pancreatic cancer cell lines and paraffinized tissue of 129 pancreatic carcinomas were immunostained for PPARg.For statistical analysis, Fisher’s exact test, m2 test for trends, correlation analysis, Kaplan-Meier analysis, and Cox’s regression were applied. Results: Expression profiles showed a strong overexpression of PPARg mRNA (change fold, 6.9; P = 0.04). Immunohistochemically, PPARg expression was seen in 71.3% of pancreatic cancer cases. PPARg expression correlated positively to higher pTstages and higher tumor grade. Survival analysis showed a significant prognostic value for PPARg, which was found to be independent in the clinically important subgroup of node-negative tumors. Conclusions: PPARg is commonly up-regulated in pancreatic ductal adenocarcinoma and might be a prognostic marker in this disease. Both findings corroborate the importance of PPARg in tumor progression of pancreatic cancer.
    [Show full text]
  • The Histone Acetylase PCAF Is a Nuclear Receptor Coactivator
    Downloaded from genesdev.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press The histone acetylase PCAF is a nuclear receptor coactivator Jorge C.G. Blanco,1,4 Saverio Minucci,1 Jianming Lu,1 Xiang-Jiao Yang,1 Kristen K. Walker,3 Hongwu Chen,3 Ronald M. Evans,2,3 Yoshihiro Nakatani,1 and Keiko Ozato1,5 1Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, Maryland 20892-2753 USA; 2Howard Hughes Medical Institute; 3The Salk Institute for Biological Studies, La Jolla, California 92037 USA Whereas the histone acetylase PCAF has been suggested to be part of a coactivator complex mediating transcriptional activation by the nuclear hormone receptors, the physical and functional interactions between nuclear receptors and PCAF have remained unclear. Our efforts to clarify these relationships have revealed two novel properties of nuclear receptors. First, we demonstrate that the RXR/RAR heterodimer directly recruits PCAF from mammalian cell extracts in a ligand-dependent manner and that increased expression of PCAF leads to enhanced retinoid-responsive transcription. Second, we demonstrate that, in vitro, PCAF directly associates with the DNA-binding domain of nuclear receptors, independently of p300/CBP binding, therefore defining a novel cofactor interaction surface. Furthermore, our results show that dissociation of corepressors enables ligand-dependent PCAF binding to the receptors. This observation illuminates how a ligand-dependent receptor function can be propagated to regions outside the ligand-binding domain itself. On the basis of these observations, we suggest that PCAF may play a more central role in nuclear receptor function than previously anticipated.
    [Show full text]
  • Retinoic Acid-Related Orphan Receptor Rorβ, Circadian Rhythm Abnormalities and Tumorigenesis (Review)
    INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 35: 1493-1500, 2015 Retinoic acid-related orphan receptor RORβ, circadian rhythm abnormalities and tumorigenesis (Review) SHUJIONG FENG1, SONG XU1, ZHENZHEN WEN1 and YONGLIANG ZHU1,2 1Laboratory of Gastroenterology, The Second Affiliated Hospital of Zhejiang University, School of Medicine; 2Cancer Institute and Education Ministry Key Laboratory of Cancer Prevention and Intervention, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China Received August 8, 2014; Accepted March 12, 2015 DOI: 10.3892/ijmm.2015.2155 Abstract. Nuclear receptors are a superfamily of transcription and have important physiological functions in cell develop- factors including the steroid hormone receptors, non-steroid ment and differentiation, circadian rhythm, metabolism and hormone receptors and the orphan nuclear receptor family. immune regulation. NRs consist of three components: the Retinoic acid-related orphan receptor (ROR)β, as a member of steroid hormone receptors, non-steroid hormone receptors the orphan nuclear receptor family, plays an important regula- and the orphan nuclear receptor family. Steroid and non- tory role in the maintenance of a variety of physiological and steroid hormone receptors have specific ligands, including pathological processes. RORβ has been determined to act as steroid hormones, thyroid hormones, retinoic acids and fatty an osteogenic repressor in regulating bone formation, and is acids. Ligands for orphan NRs have not yet been determined. involved in regulating circadian rhythm. The findings of recent Retinoic acid-related orphan receptors (RORs), also known studies concerning the association between tumorigenesis as nuclear receptor subfamily 1 group F members (NR1F), and circadian rhythm have shown that an aberrant circadian are specified by gene sequences, which are homologous to rhythm may promote tumorigenesis and tumor progression.
    [Show full text]
  • Cooperative Interaction Between Retinoic Acid Receptor-A and Estrogen Receptor in Breast Cancer
    Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Cooperative interaction between retinoic acid receptor-a and estrogen receptor in breast cancer Caryn S. Ross-Innes,1 Rory Stark,2 Kelly A. Holmes,1 Dominic Schmidt,1 Christiana Spyrou,1 Roslin Russell,2 Charlie E. Massie,1 Sarah L. Vowler,2 Matthew Eldridge,2 and Jason S. Carroll1,3 1Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, United Kingdom; 2Bioinformatics Core, Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, United Kingdom Retinoic acid receptor-a (RARa) is a known estrogen target gene in breast cancer cells. The consequence of RARa induction by estrogen was previously unknown. We now show that RARa is required for efficient estrogen receptor-a (ER)-mediated transcription and cell proliferation. RARa can interact with ER-binding sites, but this occurs in an ER-dependent manner, providing a novel role for RARa that is independent of its classic role. We show, on a genome-wide scale, that RARa and ER can co-occupy regulatory regions together within the chromatin. This transcriptionally active co-occupancy and dependency occurs when exposed to the predominant breast cancer hormone, estrogen—an interaction that is promoted by the estrogen–ER induction of RARa. These findings implicate RARa as an essential component of the ER complex, potentially by maintaining ER–cofactor interactions, and suggest that different nuclear receptors can cooperate for effective transcriptional activity in breast cancer cells. [Keywords: Breast cancer; estrogen receptor; retinoic acid receptor-a; transcription; chromatin] Supplemental material is available at http://www.genesdev.org.
    [Show full text]
  • Retinoid-Induced Apoptosis in Normal and Neoplastic Tissues
    Cell Death and Differentiation (1998) 5, 11 ± 19 1998 Stockton Press All rights reserved 13509047/98 $12.00 Review Retinoid-induced apoptosis in normal and neoplastic tissues Laszlo Nagy1,3,4, Vilmos A. Thomazy1, Richard A. Heyman2 retinoic acid receptor (RAR), which belongs to the superfamily and Peter J.A. Davies1,3 of ligand-activated transcription factors (nuclear receptors) revolutionized our understanding as to how retinoids exert 1 Department of Pharmacology, University of Texas-Houston, Medical School, their pleiotropic effects (for reviews see Chambon (1996); Houston, Texas 77225 USA Mangelsdorf et al (1994)). Members of the nuclear receptor 2 Ligand Pharmaceuticals, San Diego, California, 92121 USA superfamily mediate the biological effects of many hormones, 3 Corresponding author: PJAD, tel: 713-500-7480; fax: 713-500-7455; vitamins and drugs (i.e. steroid hormones, thyroid hormones, e-mail: [email protected] 4 vitamin D, prostaglandin-J (PG-J ) and drugs that activate Present address for correspondence: The Salk Institute for Biological Studies, 2 2 Gene Expression Laboratory, La Jolla, California 92037; peroxisomal proliferation). There are two families of retinoid tel: (619) 453-4100 fax:(619) 455-1349; e-mail: [email protected] receptors, Retinoid X Receptors (RXRs) that bind 9-cis retinoic acid (9-cis RA) and Retinoic Acid Receptors (RARs) Received 18.8.97; revised 19.9.97; accepted 22.9.97 that bind both 9-cis RA and all-trans retinoic acid (ATRA) (for Edited by M. Piacentini reviews see Chambon 1996; Mangelsdorf et al, 1994)). Each of these receptor families includes at least three distinct genes, (RARa,b and g; RXRa,b and g) that through differential Abstract promoter usage and alternative splicing, give rise to a large number of distinct retinoid receptor proteins (for reviews see Vitamin A and its derivatives (collectively referred to as Chambon 1996; Mangelsdorf et al, 1994).
    [Show full text]
  • The Orphan Receptor Rev-Erbaot Activates Transcription Via a Novel Response Element HEATHER P
    MOLECULAR AND CELLULAR BIOLOGY, May 1993, p. 3113-3121 Vol. 13, No. 5 0270-7306/93/053113-09$02.00/0 Copyright © 1993, American Society for Microbiology The Orphan Receptor Rev-ErbAot Activates Transcription via a Novel Response Element HEATHER P. HARDING AND MITCHELL A. LAZAR* Endocrinology Division, Department ofMedicine, and Department of Genetics, University ofPennsylvania School ofMedicine, Philadelphia, Pennsylvania 19104 Received 18 December 1992/Returned for modification 1 February 1993/Accepted 11 February 1993 Rev-ErbAca (Rev-Erb) is a nuclear hormone receptor-related protein encoded on the opposite strand of the at-thyroid hormone receptor (TR) gene. This unusual genomic arrangement may have a regulatory role, but the conservation of human and rodent Rev-Erb amino acid sequences suggests that the protein itself has an important function, potentially as a sequence-specific transcriptional regulator. However, despite its relation- ship to the TR, Rev-Erb bound poorly to TR binding sites. To determine its DNA-binding specificity in an unbiased manner, Rev-Erb was synthesized in Escherichia coli, purified, and used to select specific binding sites from libraries of random double-stranded DNA sequences. We found that Rev-Erb binds to a unique site consisting of a specific 5-bp A/T-rich sequence adjacent to a TR half-site. Rev-Erb contacts this entire asymmetric 11-bp sequence, which is the longest nonrepetitive element specifically recognized by a member of the thyroid/steroid hormone receptor superfamily, and mutations in either the A/T-rich or TR half-site regions abolished specific binding. The binding specificity of wild-type Rev-Erb was nearly identical to that of C- and N-terminally truncated forms.
    [Show full text]
  • Blocking Activator Protein-1 Activity, but Not Activating Retinoic Acid Response Element, Is Required for the Antitumor Promotion Effect of Retinoic Acid
    Proc. Natl. Acad. Sci. USA Vol. 94, pp. 5826–5830, May 1997 Medical Sciences Blocking activator protein-1 activity, but not activating retinoic acid response element, is required for the antitumor promotion effect of retinoic acid CHUANSHU HUANG*, WEI-YA MA*, MARCIA I. DAWSON†,MERCEDES RINCON‡,RICHARD A. FLAVELL‡, AND ZIGANG DONG*§ *The Hormel Institute, University of Minnesota, 801 16th Avenue, N.E., Austin, MN 55912; †Retinoid Program, SRI International, Menlo Park, CA 94025; and ‡Section of Immunology, Howard Hughes Medical Institute, Yale University School of Medicine, P.O. Box 3333, New Haven, CT 06510 Communicated by Ralph T. Holman, University of Minnesota, Austin, MN, March 31, 1997 (received for review February 10, 1997) ABSTRACT Retinoic acid is one of the most promising in tumor promotion and the mechanism of some chemopre- drugs for chemotherapy and chemoprevention of cancer. ventional drugs in animal models. Either blocking activator protein-1 (AP-1) activity or activat- Retinoids can inhibit tumor cell growth and induce the ing retinoic acid response element (RARE) have been pro- differentiation and reversion of certain malignant cells to posed to be responsible for its antitumor activity. However, normal phenotype (21, 22). Retinoic acid has been proven to evidence for this hypothesis is lacking in vivo studies. To be effective in inhibiting papilloma formation in a mouse address this issue, we used an AP-1-luciferase transgenic model and tumor promoter-induced transformation in JB6 mouse as a carcinogenesis model and new synthetic retinoids cells (21, 23–26). Clinical studies indicated that retinoic acid is that are either selective inhibitors of AP-1 activation or effective for treatment of certain types of leukemia (27, 28) selective activators of the RARE.
    [Show full text]
  • Retinoid X Receptors: X-Ploring Their (Patho)Physiological Functions
    Cell Death and Differentiation (2004) 11, S126–S143 & 2004 Nature Publishing Group All rights reserved 1350-9047/04 $30.00 www.nature.com/cdd Review Retinoid X receptors: X-ploring their (patho)physiological functions A Szanto1, V Narkar2, Q Shen2, IP Uray2, PJA Davies2 and aspects of metabolism. The discovery of retinoid receptors L Nagy*,1 substantially contributed to understanding how these small, lipophilic molecules, most importantly retinoic acid (RA), exert 1 Department of Biochemistry and Molecular Biology, Research Center for their pleiotropic effects.1,2 Retinoid receptors belong to the Molecular Medicine, University of Debrecen, Medical and Health Science family of nuclear hormone receptors, which includes steroid Center, Nagyerdei krt. 98, Debrecen H-4012, Hungary 2 hormone, thyroid hormone and vitamin D receptors, various Department of Integrative Biology and Pharmacology, The University of Texas- orphan receptors and also receptors activated by intermediary Houston Medical School, Houston, TX, USA * Corresponding author: L Nagy, Department of Biochemistry and Molecular metabolites: for example, peroxisome proliferator-activated Biology, University of Debrecen, Medical and Health Science Center, receptor (PPAR) by fatty acids, liver X receptor (LXR) by Nagyerdei krt. 98, Debrecen H-4012, Hungary. Tel: þ 36-52-416432; cholesterol metabolites, farnesoid X receptor (FXR) by bile Fax: þ 36-52-314989; E-mail: [email protected] acids and pregnane X receptor (PXR) by xenobiotics.3,4 Members of this family function as ligand-activated
    [Show full text]
  • Role of Vitamin A/Retinoic Acid in Regulation of Embryonic and Adult Hematopoiesis
    nutrients Review Role of Vitamin A/Retinoic Acid in Regulation of Embryonic and Adult Hematopoiesis Ana Cañete 1, Elena Cano 2, Ramón Muñoz-Chápuli 1 and Rita Carmona 1,* 1 Department of Animal Biology, Faculty of Science, University of Malaga, Campus de Teatinos s/n Malaga 29071, Spain and Andalusian Center for Nanomedicine and Biotechnology (BIONAND), Severo Ochoa 25, Campanillas 29590, Spain; [email protected] (A.C.); [email protected] (R.M.-C.) 2 Max-Delbruck Center for Molecular Medicine, Robert Roessle-Strasse 10, 13125 Berlin, Germany; [email protected] * Correspondence: [email protected]; Tel.: +34-952134135; Fax: +34-952131668 Received: 23 October 2016; Accepted: 16 February 2017; Published: 20 February 2017 Abstract: Vitamin A is an essential micronutrient throughout life. Its physiologically active metabolite retinoic acid (RA), acting through nuclear retinoic acid receptors (RARs), is a potent regulator of patterning during embryonic development, as well as being necessary for adult tissue homeostasis. Vitamin A deficiency during pregnancy increases risk of maternal night blindness and anemia and may be a cause of congenital malformations. Childhood Vitamin A deficiency can cause xerophthalmia, lower resistance to infection and increased risk of mortality. RA signaling appears to be essential for expression of genes involved in developmental hematopoiesis, regulating the endothelial/blood cells balance in the yolk sac, promoting the hemogenic program in the aorta-gonad-mesonephros area and stimulating eryrthropoiesis in fetal liver by activating the expression of erythropoietin. In adults, RA signaling regulates differentiation of granulocytes and enhances erythropoiesis. Vitamin A may facilitate iron absorption and metabolism to prevent anemia and plays a key role in mucosal immune responses, modulating the function of regulatory T cells.
    [Show full text]