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Polypeptide Hormone Regulation of Gene Transcription

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Polypeptide Hormone Regulation of Gene Transcription Proc. Natl. Acad. Sci. USA Vol. 81, pp. 2975-2979, May 1984 Biochemistry Polypeptide hormone regulation of gene transcription: Specific 5' genomic sequences are required for epidermal growth factor and phorbol ester regulation of prolactin gene expression (pituitary/DNA-mediated gene transfer) SCOTT C. SUPOWIT*t, ELLEN POTTER*t, RONALD M. EVANSt, AND MICHAEL G. ROSENFELD* *Eukaryotic Regulatory Biology Program, University of California, San Diego, School of Medicine, La Jolla, CA 92093; and tMolecular Biology and Virology Laboratory, The Salk Institute, La Jolla, CA 92138 Communicated by Daniel Steinberg, January 23, 1984 ABSTRACT A fusion gene containing 5' rat prolactin ge- these genes by various regulatory agents outside their nor- nomic sequences ligated to the structural portion of the rat mal cellular and chromosomal environment (13, 14). By us- growth hormone gene (grl) was introduced by DNA-mediated ing transfectional analysis, it has been demonstrated that gene transfer into mammalian cells by using a chimeric plas- DNA sequences located 5' to the so-called "TATA" box and mid vector. Clonal transfected cell lines produced a mRNA RNA cap site are necessary for efficient and accurate RNA that used the authentic 5' initiation site and that was processed polymerase 11-catalyzed transcription of many eukaryotic to the predicted size. The intracellular levels of this RNA prod- genes, in vivo and in vitro (15-17). This technology also per- uct were increased 2.5- to 5-fold by exposure of the cells to mitted the evaluation of the hypothesis that specific genomic epidermal growth factor (EGF) and 2- to 3-fold by exposure of regions are responsible for hormonal and metabolic regula- the cells to a potent phorbol ester, phorbol 12-myristate 13- tion of gene expression (18-28). Transfer of regulation has acetate, apparently due to regulation at the level of gene tran- been reported in the case of steroid hormones (18-23), scription. Substitution of the 5' prolactin DNA sequences by 5' poly(rI)poly(rC) (24), and heavy metal (25) regulation of growth hormone DNA sequences resulted in the loss of EGF specific genes. inducibility. A genomic sequence in or near the 5' flanking We therefore employed DNA-mediated gene transfer to portion of the prolactin gene therefore appears to confer poly- determine whether specific genomic sequences are required peptide hormone transcriptional regulation upon the gene. for polypeptide hormone regulation upon responsive genes. A fusion gene containing 5' flanking prolactin genomic infor- Polypeptide hormones and neuropeptides represent a di- mation and growth hormone coding regions (grl) was ex- verse class of intercellular regulatory substances. They are pressed with correct initiation and RNA processing events, critical for development and homeostatic control, and they in a human cell line rich in EGF receptors. The gene product act to regulate the expression of specific genes (e.g., see was induced by the peptide hormone, EGF, apparently ex- refs. 1-6). To understand the events by which the binding of erting transcriptional effects, and by a phorbol ester. Substi- a peptide hormone to the plasma membrane receptor initi- tution of 5' prolactin genomic sequences with comparable 5' ates events that can rapidly (within 1-2 min) modulate gene sequences from a nonresponsive gene (growth hormone) transcription (4-6), it is necessary to define whether a spe- abolishes the transfer of hormonal regulation. cific genomic sequence is required and sufficient for confer- ring the effects of polypeptide regulators on gene transcrip- METHODS tion. Cell Culture and DNA Transfection. Human A431 cells In clonal rat pituitary tumor cell lines (GH) (7) thyrotro- were maintained in Dulbecco's modified Eagle's medium pin-releasing hormone (TRH), a hypothalamic tripeptide, containing 1% fetal calf serum. Supercoiled plasmid DNA and epidermal growth factor (EGF), a small polypeptide was introduced into cultured cells by using the calcium phos- originally isolated from the submaxillary glands of male phate precipitation technique (29) followed by a glycerol mice, increase the production of prolactin (8, 9) and prolac- shock after 4 hr (30); neomycin-resistant cells were selected tin mRNA (2-5). We have demonstrated that both EGF and by growth in the presence ofthe antibiotic G418 at 400 ,ug/ml TRH act at the nuclear level to rapidly increase the tran- (31). Individual foci of transformed cells were maintained in scription of the prolactin gene (5, 6). In addition, phorbol the presence of G418 at 200 ,Ag/ml. esters produce effects on GH cells, such as cell shape Analysis of RNA and DNA. Purified genomic DNA restric- change, growth alterations, and increased prolactin biosyn- tion fragments were resolved by electrophoresis of 0.8% thesis, similar to those produced by EGF and TRH (10). We agarose gels and then transferred to nitrocellulose by the find that phorbol esters increase prolactin mRNA levels, method of Southern (32). Total cellular RNA was isolated (2) prolactin gene transcription, and phosphorylation of a basic and DNA was removed by two precipitations with 2 M nuclear protein (BRP) in a fashion comparable to the effects LiCl/10 mM sodium acetate, pH 5.5 (33). DNA content of all of EGF or TRH (5-11). Phorbol esters such as phorbol 12- RNA samples was determined by a fluorometric assay using myristate 13-acetate (PMA) appear to directly activate a the DNA dye Hoechst 33258 (34). Samples (10,g) were ana- Ca2'- and phospholipid-dependent protein kinase, referred lyzed by fractionation using denaturing gel electrophoresis, to as protein kinase C' (12). blotting, and DNA-excess hybridization as described (4). DNA-mediated transfer of regulated eukaryotic genes into The 5' end of the growth hormone cDNA-reactive RNAs heterologous mammalian cells provides the requisite analyt- were analyzed by using an appropriate DNA probe radiola- ic technology for studying the expression and induction of beled by replacement synthesis with T4 DNA polymerase The publication costs of this article were defrayed in part by page charge Abbreviations: TRH, thyrotropin-releasing hormone; EGF, epider- payment. This article must therefore be hereby marked "advertisement" mal growth factor; PMA, phorbol 12-myristate 13-acetate; SV40, in accordance with 18 U.S.C. §1734 solely to indicate this fact. simian virus 40; kb, kilobase(s); bp, base pair(s). 2975 Downloaded by guest on September 26, 2021 2976 Biochemistry: Supowit et aL Proc. NatL Acad Sci. USA 81 (1984) (35) and the S1 nuclease method described by Berk and Organization of the Fusion Gene DNA in Transformed Sharp (36). After hybridization with excess labeled DNA Cells. Human A431 cells were transfected with chimeric probe, the RNADNA hybrids were digested with S1 nucle- plasmids containing either the rat prolactin-growth hormone ase and subjected to electrophoresis on denaturing 8% acryl- fusion gene (pSV2ne0grl) or rat growth hormone gene amide/8 M urea sequencing gels (37). The nuclear run-off (pSV2ne0GH). Hirt DNA extracts (41) prepared from several transcription assay was performed as previously described of the stable pSV2neogrl-transfected cell lines revealed no ex- (4, 5) using 7 x 107 cpm per hybridization, and growth hor- trachromosomal neo or grl DNA. Transfected DNA se- mone cDNA was inserted into M13 phage DNA as probe. quences derived from the chimeric gene were detected in the chromosomal DNA of the transformed cell lines by analysis RESULTS of HindIII-digested genomic DNA. DNA from the parental Construction of Chimeric Rat Prolactin Genomic Clones for A431 cell line shows two strongly hybridizing high molecular Transfectional Analysis. A simian virus 40 (SV40) hybrid plas- weight (>20 kb) HindIII genomic fragments, reflecting en- mid vector pSV2neo that contained the dominant selectable dogenous growth hormone genes (Fig. 2). A unique 5.7-kb marker Tn5 phosphotransferase (neo) (31) was modified to HindIII fragment present in the intact plasmid, which spans contain a fusion gene in which the 5' regions ofthe growth hor- the entire grl gene, including 5' and 3' flanking sequences, is mone gene, a gene that is not induced by EGF, were replaced present in 6 of the 10 pSVneogrl-containing clonal cell lines with 5' prolactin genomic sequences (38, 39) in such a way analyzed, with an estimated chromosomally integrated copy that mRNA transcribed from this gene should contain the number of 1-4 in different cell lines (Fig. 2). In one cell line, information encoded in the first prolactin genomic exon and instead of the 5.7-kb band, a slightly smaller (5.1-kb) band the second through fifth rat growth hormone genomic exons was visualized (grl d). In addition, the cell lines contained a (see Fig. 1). Analysis of the sequences of the first prolactin wide variety of additional reactive HindIlI fragments ranging "donor" splice site and the first growth hormone "acceptor" in size from 3.8 to >20 kb (see Fig. 2). These heterogeneous site showed that they contained the requisite G-T ... A-G fragments are likely to have resulted from integration of the sequences under "Chambon" rules of splicing (40). There- chimeric plasmid DNA at sites within the 5.7-kb HindIII re- fore, if the prolactin gene contains a regulatory element for gion into variable integration sites of flanking A431 cellular EGF induction within or near the 5' nonflanking sequences, DNA sequences. These data indicate that most lines have the fusion gene (gri) should be productive of an EGF- or multiple integrated copies of both intact and modified grl fu- PMA-inducible mRNA containing the cap site and 82 nucleo- sion genes, integrated into a wide variety of genomic sites. tides of prolactin mRNA (exon I) followed by growth hor- One line (grl i) appears to have a single integrated copy ofthe mone mRNA sequences transcribed from exons 2 through 5 gene. of the growth hormone gene.
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