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Activation of the Cytotactin Promoter by the Homeobox-Containing Gene

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Activation of the Cytotactin Promoter by the Homeobox-Containing Gene Proc. Natl. Acad. Sci. USA Vol. 89, pp. 2091-2095, March 1992 Developmental Biology Activation of the cytotactin promoter by the homeobox-containing gene Evx-1 (morphogenesis/extracellular matrix/phorbol 12-O-tetradecanoate 13-acetate response element/homeodomain/growth factors) FREDERICK S. JONES*, GEORGES CHALEPAKISt, PETER GRUSSt, AND GERALD M. EDELMAN* *Laboratory of Developmental and Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10021; and tDepartment of Molecular Cell Biology, Max Planck Institute of Biophysical Chemistry, 3400 Gottingen, Federal Republic of Germany Contributed by Gerald M. Edelman, December 17, 1991 ABSTRACT Cytotactin is a morphoregulatory molecule of during development in place-dependent patterns that corre- the extracellular matrix affecting cell shape, division, and spond to morphologically significant boundaries (3-6). Cy- migration that appears in a characteristic and complex site- totactin has been shown to affect a variety of processes restricted pattern during embryogenesis. The promoter region including cell spreading or rounding, adhesion and repulsion, of the gene that encodes chicken cytotactin contains a variety and neurite retraction; it can also modulate mitogenesis (4, of potential regulatory sequences. These include putative bind- 7-14). The multifunctionality ofthe molecule may reside in its ing sites for homeodomain proteins and a phorbol 12-0- modular structure (10, 15-19) that contains many indepen- tetradecanoate 13-acetate response element (TRE)/AP-1 ele- dent binding domains. A key question is how the site- ment, a potential target for transcription factors thought to be restricted expression ofcytotactin is genetically controlled in involved in growth-factor signal transduction. To determine a fashion sufficient to assure normal morphogenesis. Ho- the effects of homeobox-containing genes on cytotactin pro- meobox-containing genes appear to be excellent candidates moter activity, we conducted a series of cotransfection exper- for the control of such morphoregulatory molecules, given iments on NIH 3T3 cells using cytotactin promoter- the evidence that they affect neighborhood-specific develop- chloramphenicol acetyltransferase (CAT) reporter gene con- mental patterns in various embryonic axes (20-24). We have structs and plasmids driving the expression ofmouse homeobox described (25) modulation of the expression of N-CAM, the genes Evx-1 and Hox-1.3. Cotransfection withEvx-1 stimulated neural cell adhesion molecule, by Hox genes. The presence cytotactin promoter activity whereas cotransfection in control of sequence motifs resembling homeodomain binding sites in experiments with Hox-1.3 had no effect. To localize the se- the 5' flanking sequence of the cytotactin gene prompted us quences required for Evx-1 activation, we tested a series of to examine cytotactin in a similar fashion. deletions in the cytotactin promoter. An 89-base-pair region We report here that Evx-J, a mouse homeobox gene most containing a consensus TRE/AP-1 element was found to be related to the pair-rule gene even-skipped (eve) from Dro- required for activation. An oligonucleotide segment containing sophila melanogaster (26), induces the expression in NIH this TRE/AP-1 site was found to confer Evx-l inducibility on 3T3 cells of a chloramphenicol acetyltransferase (CAT) re- a simian virus 40 minimal promoter; mutation of the porter gene driven by the chicken cytotactin promoter. TRE/AP-1 site abolished this activity. To explore the potential Deletion analysis performed on the cytotactin promoter role of growth factors in cytotactin promoter activation, region localized the sequences that contributed to the acti- chicken embryo fibroblasts, which are known to synthesize vation to an 89-base-pair (bp) segment containing a phorbol cytotactin, were frnst transfected with cytotactin promoter 12-O-tetradecanoate 13-acetate response element (TRE)/ constructs and cultured under minimal conditions in 1% fetal AP-1 element. This control element has been shown to be a bovine serum. Although the cells exhibited only low levels of target for transcription factors encoded by the fos and jun CAT activity under these conditions, cells exposed for 12 h to gene families (27-29). Mutation of the TRE/AP-1 sequence 10% (vol/vol) fetal bovine serum showed a marked increase in abolished the ability of Evx-J to activate the promoter. The CAT activity. Cotransfection with Evx-1 and cytotactin pro- TRE/AP-1 element was also required to drive expression of moter constructs of cells cultured in 1% fetal bovine serum was the CAT reporter gene in chicken embryo fibroblasts, cells sufficient, however, to produce high levels of CAT activity. known to synthesize cytotactin. Furthermore, transfection These findings are consistent with the hypothesis that Evx-1, a with Evx-J obviated the requirement for the higher concen- homeobox-containing gene, may activate the cytotactin pro- tration of serum otherwise necessary to activate cytotactin moter by a mechanism involving a growth-factor signal trans- promoter constructs containing the TRE/AP-1 site. duction pathway. More generally, the results support the These results, along with those obtained with the N-CAM hypothesis that the place-dependent expression of morphoreg- promoter (25), provide support for the hypothesis that the ulatory molecules may depend upon local cues provided by expression ofmorphoregulatory molecules may be controlled homeobox genes and their encoded proteins. by homeobox gene products. In addition, they raise the possibility that the cytotactin promoter modulation by Evx-J During development, metamorphosis, and regeneration, a may involve a growth-factor signal transduction pathway. number of different morphoregulatory molecules mediating cell and substrate adhesion and junction formation are ex- pressed in defined sequences (1). These molecules act to MATERIALS AND METHODS regulate primary cellular processes such as movement, divi- CAT gene reporter plasmids were constructed in BSCAT, a sion, and cell-cell communication in a place-dependent fash- Bluescript vector (Stratagene) containing a 1.8-kilobase CAT ion (2). A remarkable example of such a molecule is cyto- gene, and also in commercially available pCAT-Basic and tactin/tenascin, an extracellular matrix protein that appears pCAT-Promoter vectors (Promega). Restriction fragments The publication costs of this article were defrayed in part by page charge Abbreviations: CAT, chloramphenicol acetyltransferase; SV40, sim- payment. This article must therefore be hereby marked "advertisement" ian virus 40; CMV, cytomegalovirus; TRE, phorbol 12-0- in accordance with 18 U.S.C. §1734 solely to indicate this fact. tetradecanoate 13-acetate response element. 2091 Downloaded by guest on September 30, 2021 2092 Developmental Biology: Jones et al. Proc. Natl. Acad. Sci. USA 89 (1992) 1 2 3 4 5 6 7 8 9 10 11 12 Mouse homeobox genes Evx-J and Hox-1.3 were inserted into cytomegalovirus (CMV) and 83-actin promoter vectors, respectively. In cotransfection experiments, these plasmids, designated CMV-Evx-1 and fBA-Hox-1.3, were used as pro- S.0*.. 0 ducers ofthe homeodomain proteins in situ. Test DNAs were -* f transfected into cells with Bluescript carrier DNA, as de- scribed (25). NIH 3T3 cells were maintained in Dulbecco's modified Eagle's medium supplemented with 10%o (vol/vol) * @[email protected]. calf serum. Chicken embryo fibroblasts were prepared from 11-day body walls as described (31). Transfectants were harvested 36-72 h after transfection and assayed for CAT activity. Cells were cotransfected with 5 jg of RSV-f3- galactosidase plasmid DNA and extracts were normalized for FIG. 1. Activation of cytotactin promoter activity in NIH 3T3 internal fB-galactosidase activity as described (25). DNase I cells after cotransfection with Evx-1. NIH 3T3 cells were cotrans- footprinting was performed using the fushi tarazu (ftz) ho- fected with 10 ,ug of reporter gene plasmid and with various amounts meodomain protein as described (32). of homeobox gene expression plasmids. Cells were harvested 72 h after transfection and assayed for CAT activity. Reporter plasmids for cotransfections were added as follows: CTP7-CAT (lanes 1-9), RESULTS BSCAT (lanes 10 and 11), and SV40 promoter/enhancer-BSCAT (lane 12). Homeobox gene expression plasmids were transfected in Activation of the Cytotactin Promoter by Evx-1. To test the following concentrations. CMV-Evx-1, 1 jg (lane 2), 2 ,ug (lane whether Evx-1 or Hox-1.3 genes could affect the activity of 3), 5 ,ug (lane 4), and 10 ,ug (lanes 5 and 10); ,BA-Hox-1.3, 1 ,ug (lane the cytotactin promoter, NIH 3T3 cells were cotransfected 6), 2 ,ug (lane 7), 5 ug (lane 8), and 10 ,ug (lanes 9 and 11). with the cytotactin promoter-CAT reporter gene plasmid CTP7-CAT and either the CMV-Evx-l or the /BA-Hox-1.3 from the 5' end and upstream flanking region of the chicken expression plasmids and were then assayed for CAT activity. cytotactin gene that were used to prepare reporter constructs Cells transfected with CMV-Evx-l had significant CAT ac- were derived from plasmids as described (30). Reporter tivity driven by the cytotactin promoter (Fig. 1, compare constructs were designated according to the cytotactin pro- lanes 2-5 to lane 1) but controls transfected with Hox-1.3 moter segments used; the numbers in parentheses refer to showed no detectable CAT activity (Fig. 1, compare lanes positions either upstream (-) or downstream (+) from the 6-9 to lane 1). site of transcription initiation. Reporters used in this study Analysis ofthe Cis Sequences Required forEvx-1 Activation. (-3986 to +374), CTP12-CAT To define further the regions of the cytotactin promoter that were as follows: CTP7-CAT were critical for Evx-1 activation, cytotactin promoter dele- (-1477 to -201), CTP4-CAT (-1312 to +270), CTP3-CAT tion constructs (Fig. 2) were tested for their ability to be (-936 to +121), CTP2-CAT (-289 to +374), and CTP14- activated by CMV-Evx-l after cotransfection in NIH 3T3 CAT (-201 to +121). In addition, one or two copies of a cells.
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