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Retinoic Acid Receptors and Retinoid X Receptors: Interactions With Proc. Nati. Acad. Sci. USA Vol. 90, pp. 30-34, January 1993 Biochemistry Retinoic acid receptors and retinoid X receptors: Interactions with endogenous retinoic acids (afl-ftns-retinoic acid/9-cis-retinoic acid/3,4-didehydroretinoic add/binding affinity/transcriptional activation) GARY ALLENBY*, MARIE-THERESE BOCQUELt, MICHAEL SAUNDERSt, SONJA KAZMER*, JEFFREY SPECK*, MICHAEL ROSENBERGERf, ALLEN LOVEY*, PHILIPPE KASTNERt, JOSEPH F. GRIPPO*, PIERRE CHAMBONt, AND ARTHUR A. LEVIN*§ *Department of Toxicology and Pathology and tDepartment of Medicinal Chemistry, Hoffmann-La Roche, Nutley, NJ 07110; and Institut de Chimie Biologique, Unite 184 de Biologie Mol6culaire et de G6nie G6netique de l'Institut National de la Sante et de la Recherche M6dicale, Laboratoire de G6n6tique Mol6culaire des Eucaryotes du Centre National de la Recherche Scientifique, Facult6 de M6decine, 11 rue Humann, 67085 Strasbourg Cedex, France Contributed by Pierre Chambon, August 14, 1992 ABSTRACT The binding of endogenous retinoids and Another factor controlling the pleiotropic effects of retin- stereoisomers of retinoic add (RA) to the retinoid nuclear oids may be the existence of multiple ligand pathways for the receptors, RA receptor (RARs) and retinoid X receptors retinoid receptors. The RARs directly bind all-trans-RA (RXRs), was characterized using nucleosol preparations from (t-RA) and as a consequence of this binding become tran- transiently transfected COS-1 cells. Among several stereoiso- scriptionally active. The RXRs differ from the RARs in that mers ofRA tested, including 7-cis-, 9-cis-, 11-cis-, 13-cis-, and they are incapable of binding t-RA, but they bind and are all-trns-RA, only 9-cis-RA effectively competes with 9-cis- activated by the 9-cis stereoisomer of RA (20, 21). The [3HJRA binding to the RXRs. Additionally, the endogenous 3,4-didehydro form of t-RA (t-ddRA) is also biologically retinoid trans-didehydro-RA (t-ddRA) does not interact with active and is found in the chicken limb (22) and in mammalian RXRs, whereas the 9-cis form of ddRA competes effectively. tissues (23, 24). It is not known whether t-ddRA has a unique RXRs (a, (, and 'y) bind 9-cts-RA with dissociation constants receptor or whether its effects are mediated by interactions (Kd) of 15.7, 18.3, and 14.1 nM, respectively. In contrast to the with one of the RARs or RXRs. selectivity of RXRs for 9-cis-RA, RARs bind both t-RA and In the present investigation, we examine the ligand spec- 9-cis-RA with high affinity, exhibitng Kd values in the 0.2-0.7 ificity of the receptors and the cellular RA binding proteins nM range for both ligands. Unlike RARs, the cellular RA (CRABPs) for RA stereoisomers and other naturally occur- bindig proteins CRARPI or CRABPH bind t-RA but do not ring retinoids. The results demonstrate that the RXRs are bind 9-cis-RA. Consistent with the binding data, 9-cis-RA and selective for 9-cis-RA and 9-cis-ddRA but that the RARs 9-cis-ddRA tnscriptionally activate both GAL4-RXR and effectively bind and are activated by 9-cis-RA as well as GAL4-RAR chimeric receptors with ECso values of 3-20 nM t-RA. These results suggest a role for 9-cis-RA in the induc- for 9-cis-RA and 9-cis-ddRA, whereas t-RA and t-ddRA tion of RA target gene responses through RAR, RXR, or efficiently activate only GAIA-RAR chimeric receptors. Thus, RAR-RXR heterodimer pathways. 9-cis forms of en s retinoids can contribute to the pleiotropic effects of retinoids by interacting with both the RARs and RXRs. MATERIALS AND METHODS Materials. 9-cis-[10-3H]RA and the unlabeled RA isomers Retinoids have a broad spectrum of biological activities in were synthesized by the Department ofMedicinal Chemistry, growth and differentiation of epithelia (1), embryonic devel- Hoffmann-La Roche, and all-trans-[11,12-3H2JRA was pur- opment (2), and spermatogenesis (3). These effects are chased from NEN. HPLC analysis determined the purity of thought to result from interactions of retinoids with nuclear these reagents at >98%. receptors (4, 5) that are members of the steroid-thyroid Transfections, Nucleosol Preparations, and Binding Assays. hormone superfamily ofreceptors and as such are considered COS-1 cells were transfected by electroporation with pSG5 to be ligand-dependent transcription factors (6, 7). One expression vectors (25) containing cDNAs for mouse RARs explanation for the diversity of retinoid action resides in the a, f3, or y; RXRs a, ,B, or y; or CRABPI or CRABPII as multiplicity of nuclear receptors (for a review, see ref. 8). described (20). Nucleosol or cytosol fractions were prepared Two families of nuclear retinoid receptors have been de- (26, 27) and stored at -80°C until use. Aliquots of nucleosol scribed, the retinoic acid receptors (RARs) (4, 5, 9, 10) and or cytosol were incubated in nuclei lysis buffer (26) with the retinoid X receptors (RXRs) (11-13). These two retinoid tritiated ligands for 4 h at 4°C. Retinoids were added in receptor families are divergent, sharing only 29%6 homology ethanolic solutions that did not exceed 2% of the total in their ligand binding domains (8, 11), and may control in the incubation volume. For competitive binding assays, the form ofRAR-RXR heterodimers the expression ofRA target incubations were performed with increasing concentrations genes (12, 14-16 and references therein). They may also of unlabeled competing ligand and a fixed concentration of regulate separate gene pathways through distinct response the radioligand (10 nM 9-cis-[3H]RA). In saturation kinetics elements (17, 18). Furthermore, within the families of recep- studies, incubations were performed in the presence of tors there may be preferential activation of specific respon- increasing concentrations ofthe indicated radioligand. For all sive promoters by the different receptor types (a, ,B, or y) binding assays, bound was separated from free radioactivity (19). This multiplicity ofreceptors and gene pathways may in as described (20). Binding in the presence ofa 100-fold molar part explain the pleiotropic effects ofretinoids for the control excess of unlabeled ligand was defined as nonspecific bind- of a wide variety of cellular processes. Abbreviations: RA, retinoic acid; dd, 3,4-didehydro; t, all-trans; The publication costs ofthis article were defrayed in part by page charge RAR, RA receptor; RXR, retinoid X receptor; CRABP, cellular RA payment. This article must therefore be hereby marked "advertisement" binding protein; CAT, chloramphenicol acetyltransferase. in accordance with 18 U.S.C. §1734 solely to indicate this fact. §To whom reprint requests should be addressed. 30 Downloaded by guest on September 28, 2021 Biochemistry: Allenby et al. Proc. Natl. Acad. Sci. USA 90 (1993) 31 ing. Specific binding was defined as total binding minus (Table 1). The IC50 values for 11-cis-RA were essentially nonspecific binding. unchanged with increasing durations of incubation from 1 to The concentration required to produce a 50% inhibition of 16 h. If 11-cis-RA were being isomerized over time to binding (IC50) was calculated from competition data (28). 9-cis-RA, then the IC50 values would be expected to decrease Saturation kinetics data were analyzed as described (20, 29, with increasing incubation times (data not shown). Although 30). il-cis-RA is only a weak competitor for 9-cis-RA binding to Chimeric Receptors and Transactivation Assays. GAL4- the RXRs, it competes more efficiently for binding to the RAR a, 13, and y chimeras were constructed by PCR ampli- RXRa and RXRy forms than to the RXR/3 form (Table 1), fication of the D to F regions of mouse RAR a, 13, and y (31) suggesting that there may be differences in the ligand binding to give DNA fragments with a 5' Xho I site and a 3' Kpn I site characteristics of the RXRs. that were subcloned into the expression vector pGAL4(1- Of the RA isomers investigated, 9-cis-RA most effectively 147)ER region F (32). competes for 9-cis-[3H]RA binding to mRXRa, ,B, or y (Table The encoded chimeric GAL4-RAR 1). Interestingly, the 9-cis form of ddRA (9-cis-ddRA) com- proteins, therefore, consist of GAL4 amino acids 1-147, a petes for 9-cis-[3H]RA binding to RXRs a, 1, and 'y with IC50 short linker region encoding amino acids IGRPPRA, followed values of 210, 172, and 142 nM, respectively (data not by the RAR DEF regions linked to region F of human shown). While the 9-cis form of ddRA is an effective com- estrogen receptor amino acids 553-595 by 2 amino acids petitor, the all-trans form of ddRA, like t-RA, does not (GT), corresponding to the Kpn I site (see Fig. 4). The produce significant inhibition of 9-cis-[3H]RA binding to GAL4-RXR a, f3, and y chimeras were constructed by PCR RXRs a, 1, or y at concentrations up to 50,000 nM (data not amplification of the DE regions of mouse RXR a, 13, and y shown). Thus, the RXRs demonstrate a striking selectivity (12), followed by subcloning into GAL4MpolyII (33). The for 9-cis isomers of RA and ddRA. linker region joining the GAL4 DNA binding region to RXR We characterized the binding affinities of 9-cis-RA to sequences encodes the amino acids IPRA (see Fig. 4). The RXRs directly by saturation kinetics and Scatchard analysis. chimeric constructs were verified by DNA sequence analysis The binding of 9-cis-RA to RXRs (Fig. 1 A-C) is specific and Western blot analysis after expression in transiently and saturable. Scatchard analyses of the binding of 9-cis-RA transfected COS-1 cells.
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