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Identification of a Novel Sex Steroid Binding Protein (Receptors/Sterophilin/Chick Oviduct) ROBERT N

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Identification of a Novel Sex Steroid Binding Protein (Receptors/Sterophilin/Chick Oviduct) ROBERT N Proc. NatL Acad. Sci. USA Vol. 79, pp. 1742-1746, March 1982 Biochemistry Identification of a novel sex steroid binding protein (receptors/sterophilin/chick oviduct) ROBERT N. TAYLOR* AND RoY G. SMITHt Division of Urology (Surgery), and Department of Biochemistry and Molecular Biology, The University ofTexas Medical School at Houston, Houston, Texas 77030 Communicated by Elwood V. Jensen, November 25, 1981 ABSTRACT We describe a cytoplasmic steroid binding pro- senting the species with the higher affinity. This report de- tein in the chick oviduct which has intriguing characteristics. This scribes the identification of a new estrogen binding protein, protein binds [3H]estradiol with high affinity (Kd = 30 x 10-9 M) designated Z. and limited capacity (300 fmol/mg ofcytosol protein). It sediments at 8 S in low-salt sucrose density gradients and at 4 S in high-salt MATERIALS AND METHODS gradients. Unlike the estrogen receptor, however, this protein also Animals. Two-day-old White Leghorn pullets were pur- binds progesterone, R5020, testosterone, and 5a-dihydrotestos- chased from Texas Animal Specialties (Humble, TX), provided terone with similar affinities and in a competitive manner. More- with food and water ad lib, and raised in a constant temperature over, it is not translocated to the nucleus by the in vivo adminis- environment with a 13/11-hr light/dark schedule. At the chick tration of these sex steroids. The protein is only present in age of1 wk, estrogen stimulation was initiated by subcutaneous estrogen-responsive tissue, and like the sex steroid receptors, its insertion of two silicone implants containing 25 mg of diethyl- synthesis appears to be regulated by estrogen. stilbestrol (DES) each. Fourteen days after DES-implant in- sertion, the animals were considered fully stimulated. Periods Current molecular models of steroid hormone action suggest of estrogen withdrawal, as indicated in the text, were begun that these hormones initiate their regulatory effects by inter- after day 14 by removal ofthe DES implants through cutaneous acting with stereospecific receptor proteins localized in the cy- incisions. In some experiments, chicks were injected subcuta- tosol oftarget tissues. Steroid hormone-receptor complexes are neously 30 min before sacrifice with 2 mg each of estradiol, believed to undergo an energy-dependent activation (1) that progesterone, and 5a-dihydrotestosterone in sesame oil. All results in a conformational change and translocation into the animals were killed by decapitation; then the oviductand spleen nucleus, where regulatory interactions with the genome occur tissues were rapidly excised and processed immediately. (1-4). In the past few years, this well-accepted hypothesis has Hormones. [2,4,6,7-3H]Estradiol (90-100 Ci/mmol; 1 Ci become complicated by the discovery of steroid receptor het- = 3.7 X 101s becquerels), [1,2,6,7-3H]progesterone (89 Ci/ erogeneity (5, 6) and the demonstration of multiple steroid mmol), and [1,2,4,5,6,7-3H]5a-dihydrotestosterone (110 Ci/ binding proteins within target tissues (7, 8). The role of these mmol) were purchased from Amersham, and their purity was cytoplasmic hormone binding proteins is poorly understood, confirmed by thin-layer chromatography on silica gel plates. and the elucidation oftheir functions will be an important step Unlabeled DES, estradiol, cortisol, progesterone, testosterone, in the understanding of steroid hormone action. and 5a-dihydrotestosterone were from Sigma. Tamoxifen was In addition to the classical estrogen receptor, Clark et al. (7) a gift from Stuart Pharmaceutical (Wilmington, DE). Promege- have reported the presence ofa secondary cytoplasmic estrogen stone (R5020) was purchased from New England Nuclear. binding molecule (type II) in the rat uterus. This protein does Chemicals. "Ultra-pure" Tris base, ammonium sulfate, and not translocate into the nucleus after estradiol treatment. More- sucrose were obtained from Schwarz/Mann. Norit A charcoal, over, type II has an affinity for [3H]estradiol (Kd = 30 x 10-' 1-thioglycerol, Scintiverse, and other analytical grade reagents M) considerably weaker than that ofthe classical rat uterus es- were from Fisher. Dextran T 70 was from Pharmacia (Uppsala, trogen receptor (Kd = 0.8 x 10-9 M). A similar heterogeneity Sweden). Bio-Rad supplied hydroxylapatite. of estradiol binding molecules has been observed in mouse Preparation of Cytosol and Nuclear Extracts. Oviduct and mammary cancer tissue (8). In contradistinction to type I and spleen tissues isolated after hormonal stimulation or withdrawal type II estrogen binding proteins in rodent target tissue cytosol, were quickly excised, rinsed free ofdetectable blood in ice-cold we have reported that human uterus and chick oviduct cytosols 0.9% NaCl, and weighed. Cytosol and nuclear extracts were contain two high-affinity estrogen binding proteins, both of prepared as described (5). To obtain receptor-depleted cytosol, which have the characteristics ofreceptors (5). They have high oviducts were excised 30 min after treatment with 2.0 mg each affinities and specificity for estrogens, are present in limited of DES, dihydrotestosterone, and progesterone in sesame oil. cellular concentrations, and are found only in target tissue. Oviduct cytosols prepared from hens or hormone-stimulated Moreover, the chick oviduct estrogen receptors behave in su- chicks were treated with dextran-coated charcoal for 5 min at crose gradients with characteristic profiles, translocate stoichio- 40C to remove free steroids. The charcoal solution was prepared metrically from cytosol to nuclei in vivo, and appear to mediate as described (5). a biological estrogenic response (9, 10). Preliminary evidence [3H]Estradiol Binding Site Titration. Cytosol preparations in the human uterus suggests that each of these two receptors or redissolved 30% (NH4)2SO4-precipitated, 0.4 M KCl-ex- may have independent physiologic functions involved in the For we refer regulation ofmenstrual cyclicity (6). convenience, Abbreviations: DES, diethylstilbestrol; TESH, 10 mM Tris'HCI, pH to the two estrogen receptors as X and Y. the former repre- 7.4/1.5 mM EDTA/12 mM thioglycerol. * Present address: The University of California, San Francisco School The publication costs ofthis article were defrayed in part by page charge of Medicine, Department of Obstetrics, Gynecology and Reproduc- payment. This article must therefore be hereby marked "advertise- tive Sciences, San Francisco, CA 94143. ment" in accordance with 18 U. S. C. §1734 solely to indicate this fact. t To whom reprint requests should be addressed. 1742 Downloaded by guest on September 29, 2021 Biochemistry: Taylor and Smith Proc. Natl. Acad. Sci. USA 79 (1982) 1743 tracted nuclei were incubated in borosilicate glass tubes at 40C Each gradient was tapped from below and fractionated into 16 for 18 hr with [3H]estradiol ranging from 60 pM to 60 nM. To x 0.3 ml samples, which were directly collected into borosili- assess total nonspecific binding, we simultaneously prepared cate glass tubes at 40C. Each glass tube contained 15 pmol of a similar series ofassay tubes containing a 100-fold molar excess [3H]estradiol in 0.2 ml ofTESH. An additional series of16 tubes of unlabeled estradiol. Nuclear preparations were titrated with also contained a 100-fold molar excess ofunlabeled estradiol or [3H]estradiol in the same broad concentration range under ex- progesterone for the estimation of nonspecific binding. Gra- change (300C for 3 hr) conditions. [3H]Estradiol binding sites dient samples fractionated into these tubes were incubated at in purified whole nuclei were detected by using the nuclear 40C for 18 hr prior to the addition of 0.3 ml of dextran-coated exchange microassay as described (9). Otherwise, separation of charcoal. These suspensions were incubated for 5 min at 0WC, bound from free hormone was accomplished by dextran/char- and bound [3H] was determined as described for titration as- coal or hydroxylapatite assays. These data were plotted as de- says. Sedimentation coefficients of [3H]estradiol-binding com- scribed by Scatchard (11), providing estimates of the equilib- ponents were estimated by comparison with [14C]ovalbumin rium dissociation constant, K& and concentration of binding (3.7 S) and human y-['4C]globulin (7.0 S) standards prepared sites, Nma. Complex Scatchard curves were resolved by the as described by Rice and Means (18). method ofRosenthal (12). Cellular concentrations ofthebinding proteins were estimated on the basis of2.5 pg ofDNA per chick RESULTS AND DISCUSSION cell nucleus (13). DNA was quantitated by the diphenylamine method (14). Fig. 1 shows a typical Scatchard (11) plot of[3H]estradiol bind- Dextran-Coated Charcoal Adsorption Assay. This procedure ing in estrogen-withdrawn chick oviduct cytosol. The biphasic was based on the method described by Korenman (15) and has slope reflects the two estrogen receptors X and Y. Resolution been reported in detail by us (5). ofthese curves by the graphical method of Rosenthal (12) gave Hydroxylapatite Adsorption Assay. A method modified from equilibrium dissociation constants (Kds) of0.1 nM and 2 nM for that of Erdos et al. (16), which has been described in detail (5) X and Y, respectively. The LIGAND computer program of was used. An alternative, more rapid assay was also used. The Munson and Rodbard (19) assigned Kd values of 0.05 and 0.6 hydroxylapatite-bound receptor sample was washed with 3 ml nM to these two receptors. After estrogen administration in ofbuffer on a glass-fiber
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