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Cloning of the Chicken Progesterone Receptor (Xgt11 Expression Screening/DNA Binding Domain/V-Erba/Progesterone Receptor Forms a and B) J

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Cloning of the Chicken Progesterone Receptor (Xgt11 Expression Screening/DNA Binding Domain/V-Erba/Progesterone Receptor Forms a and B) J Proc. Natl. Acad. Sci. USA Vol. 83, pp. 5424-5428, August 1986 Biochemistry Cloning of the chicken progesterone receptor (Xgt11 expression screening/DNA binding domain/v-erbA/progesterone receptor forms A and B) J. M. JELTSCH*, Z. KROZOWSKI*t, C. QUIRIN-STRICKER*, H. GRONEMEYERt, R. J. SIMPSON§, J. M. GARNIER*, A. KRUST*, F. JACOB*, AND P. CHAMBON* *Laboratoire de Gdndtique Moleculaire des Eucaryotes du Centre National de la Recherche Scientifique et Unit6 184 de Biologie Molcularie et de Genie G6ndtique de l'Institut National de la Santd et de la Recherche Mddicale, Institut de Chimie Biologique, Facult6 de M6decine, 67085 Strasbourg Cddex, France; MLudwig Institute for Cancer Research, Bern, Switzerland; and §Joint Protein Structure Laboratory, Ludwig Institute for Cancer Research, Melbourne Tumor Biology Branch/The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia Contributed by P. Chambon, April 10, 1986 ABSTRACT Monospecific antibodies directed against the ogous to these two domains are present in the product of the chicken progesterone receptor (PR) form B were used to screen v-erbA gene of the avian erythroblastosis virus (2, 7, 9). a randomly primed phage Xgtll cDNA expression library The chicken (ref. 10 and references therein) and the human prepared from size-fractionated chicken oviduct mRNA. Two (ref. 11 and references therein) progesterone receptors (PR) independent immunoreactive clones, AcPR1 and AcPR2, were exist in two forms, A and B, both of which bind progestins isolated. Antibodies selected from anti-PR form B antiserum on and DNA. In addition, a chicken PR form B antigen that does matrices of AcPR1 and AcPR2 fusion proteins detected two not bind the hormone has been described (12), and its cDNA proteins on electrophoretic immunoblots of crude and purified has been partially cloned (13). Since there are contradictory PR preparations. These proteins had the same apparent reports concerning the relationship between these multiple molecular weights as did PR forms A and B crosslinked with the forms ofthe PR (refs. 10 and 11 and references therein), there tritiated progestin R 5020. Thus, XcPR1 and XcPR2 fusion is an obvious need to determine the primary structure ofeach proteins contain epitopes present in both PR forms A and B. A of them and, therefore, to clone the cDNAs of the hormone- cDNA done, AcPR3, containing the inserts of both AcPRl and binding forms A and B. XcPR2, was isolated from a randomly primed XgtlO oviduct With the help of affinity-labeling techniques, we have cDNA library, indicating that both cDNA inserts were derived isolated (14) the two hormone binding forms A and B of the from the same oviduct mRNA. Additional evidence that these chicken oviduct PR to apparent homogeneity and have raised cDNAs correspond to PR mRNA was provided by sequencing antibodies against both of them. Using a chicken oviduct the XcPR3 cDNA insert, since it was found to encode the Xgtll cDNA expression library and anti-PR form B antibod- ies, we now have isolated cDNA clones that contain se- sequence of three tryptic peptides prepared from purified PR quences encoding several peptides that were isolated after form B. A fourth and a fifth cDNA clone, XcPR4 and XcPR5, tryptic digestion of homogenous PR form B. Moreover, they were sequentially isolated from the same XgtlO cDNA library also encode the putative DNA-binding domain that is highly beginning with a probe derived from the 3' end of the XcPR3 conserved in the other steroid hormone receptors and in the insert. Partial DNA sequencing of XcPR4 and XcPR5 revealed product of v-erbA. However, we did not find any significant the presence of a sequence coding for a cysteine-rich domain homology between amino acid sequences deduced from the that is strikingly homologous to the amino acid sequences present cDNA clones and those deduced from the cDNA present in the putative DNA-binding domain of the human and corresponding to the nonhormone-binding receptor antigen. chicken estrogen receptors, human glucocorticoid receptor, The present study paves the way toward the elucidation of and v-erbA gene product of the avian erythroblastosis virus. the relationship between the different PR forms and structure-function studies of their various domains. In addi- Steroid hormone receptors are target cell-specific mediators tion, the present clones may be useful for cloning PR genes of the control of transcription by their respective hormones from various species, including the human species where it is during development. It is assumed that the binding of the of obvious medical interest (15, 16). steroid to the receptor induces an allosteric transition of the structure of the receptor so that it becomes capable of MATERIALS AND METHODS controlling initiation of transcription of specific genes. It is The purification of chicken oviduct PR forms A and B, their also believed that hormone-receptor complexes act as tran- photoaffinity labeling with tritiated R 5020, and the genera- scription factors by directly binding to promoter elements of tion of polyclonal anti-PR antibodies have been described hormone-responsive genes (ref. 1 and references therein). (14). Tryptic digests from apparently homogenous PR form B Thus, a detailed knowledge of the structure-function rela- were separated by using HPLC techniques, and peptides tionship of steroid hormone receptor domains is a prerequi- were sequenced at the sub-40-pmol level by using a gas-phase site to understanding hormone action at the molecular level. sequenator as will be described in detail elsewhere. Random- cDNAs corresponding to chicken (2) and human (3) estrogen ly primed phage XgtlO and Xgtll cDNA libraries were and to rat (4) and human (5, 6) glucocorticoid receptors have prepared from size-fractionated (above 4 kilobases) laying- been cloned recently. A comparison of the cDNA-deduced hen oviduct poly(A)+ mRNA as described (2, 3). Monospe- amino acid sequences of chicken (2) and human (7) estrogen cific anti-PR form B antibodies were isolated by affinity and human glucocorticoid (8) receptors has revealed a high chromatography of the crude anti-PR form B antiserum on degree of conservation in the putative DNA-binding and matrices containing covalently bound homogenous PR form hormone-binding domains (2). Moreover, sequences homol- B as described for the glucocorticoid receptor (6). For The publication costs ofthis article were defrayed in part by page charge Abbreviations: PR, progesterone receptor; bp, base pair(s). payment. This article must therefore be hereby marked "advertisement" tPresent address: Medical Research Centre, Prince Henry's Hospi- in accordance with 18 U.S.C. §1734 solely to indicate this fact. tal, Melbourne, Australia. 5424 Biochemistry: Jeltsch et al. Proc. Natl. Acad. Sci. USA 83 (1986) 5425 screening purposes and immunoblot analysis, crude as well A B C D E as monospecific anti-PR form B antisera were subtracted kDa kDa from antibody populations that crossreacted with Escherich- _ 2OO-A ia coli successive h._*. proteins by filtration through two affinity - -114- resins containing covalently bound total E. coli proteins and -a's 9- -amf* purified E. coli (3-galactosidase, respectively. The purifica- Ihe-997* W*i ..- b..... tion of fusion proteins from induced recombinant Xgtll 68 -u lysogens and the selection of antibodies on fusion protein ~~~~68-sb affinity adsorbents was performed as described (6). Screen- ing of the libraries and immunoblot analyses were done by 43433 standard procedures (3, 17, 18). Sequencing of the cDNA _ 26 clones was performed in phage M13 mp18 and mp19 by the M 12 3 4 M5 6 M 7 8 M9 10 M 1 2 1 2 3 1 2 1 2 Sanger dideoxy technique. FIG. 2. r1XcPR1~~~~~~~~~4and XcPR2 cDNA clones contain epitopes present in both PR forms A and B. (A) Coomassie blue-stained NaDodSO4/7.5% polyacrylamide gel from a crude NaDodSO4 lysate RESULTS of non-induced (lanes 1 and 3) and induced (1 mM isopropyl-P-D- Cloning of cDNA Fragments Encoding PR Form A and B thiogalactopyranoside, lanes 2 and 4), recombinant phage lysogens the Xgtll Vector. Antiserum di- specific for XcPR2 (lanes 1 and 2), and XcPR1 (lanes 3 and 4) in E. coli Epitopes Using Expression Y1089. Three immunoblots of crude lysates from isopropyl-f-D- rected against the PR form B was made monospecific by thiogalactopyranoside-induced XcPR1 (lanes 5, 7, and 9) and XcPR2 affinity chromatography on PR form B covalently coupled to (lanes 6, 8, and 10) were either stained with Coomassie blue (lanes Sepharose 4-B. A Xgtll cDNA expression library, prepared 5 and 6) or probed with monospecific anti-PR form B (lanes 7 and 8) from size-fractionated laying-hen oviduct poly(A)+ RNA (2), or preimmune serum (lanes 9 and 10). All sera were stripped ofE. coli was screened (106 clones) with these antibodies; two clones, and 3-galactosidase antibodies by filtration through corresponding XcPR1 and XcPR2 (Fig. 1), were found to express epitopes affinity resins. Each immunoblot contained purified E. coli (- recognized by monospecific anti-PR form B. The isopropyl- galactosidase in the marker lane (M) to control for crossreaction with ,B-D-thiogalactopyranoside inducible t3-galactosidase fusion /3-galactosidase. (B) Fluorograph of NaDodSO4/7.5% polyacrylam- for these two clones are shown in 2A ide gel of photoaffinity-labeled partially purified PR form A (DNA- proteins specific Fig. cellulose II fraction; see ref. 14) (lane 1) and partially purified mixture (compare lanes 1 and 2 for XcPR2 and lanes 3 and 4 for of PR forms A and B (phosphocellulose II fraction, see ref. 14) (lane XcPR1). The apparent molecular masses were approximately 2). (C) Immunoblot of a crude PR preparation (DEAE-Sepharose 125 and 130 kDa for the XcPR1- and XcPR2-speciflc fusion fraction; see ref. 14) (lane 1) and of the same partially purified PR proteins, respectively.
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