The Protooncogene c- jun Contains an Unusual Estrogen-inducible Enhancer within the Coding Sequence

Estrogens have previously been shown to induce c- jun mRNA levels in target cells during hormone induced proliferation, and this appears to be a primary hormonal response involving transcriptional activation. In this report we have now identified an estrogen dependent enhancer within the coding sequence of c- jun. This element has the sequence GCAGA nnnTGACC which is identical to the consensus estrogen response element GGTCA nnnTGACC in the second half site, but varies considerably in the first half site. Synthetic oligodeoxynucleotides containing this jun sequence bind the estrogen receptor in cell-free studies using a competitive band shift assay with the consensus element. The jun element also confers hormone inducibility to reporter plasmids in yeast and mammalian based transcriptional systems. Structure-function studies illustrate that the TGACC half-site and its immediate flanking dinucleotides, but not the GCAGA half-site, are required for estrogen receptor binding. In contrast, both the GCAGA and TGACC half-sites are obligatory for hormone-inducible transcriptional activation. These results suggest a model in which the estrogen receptor functions as a heterodimer to regulate transcription of the c- jun protooncogene. Coupled with reports of estrogen response elements in c- fos and estrogenic induction of c- fos and c- jun in vivo, these findings also support a role for AP-1 components as early response genes in estrogen-induced proliferation. Estrogens have previously been shown to induce c- jun mRNA levels in target cells during hormone induced proliferation, and this appears to be a primary hormonal response involving transcriptional activation. In this report we have now identified an estrogen dependent enhancer within the coding sequence of c- jun. This element has the sequence GCAGA nnnTGACC which is identical to the consensus estrogen response element GGTCA nnnTGACC in the second half site, but varies considerably in the first half site. Synthetic oligodeoxynucleotides containing this jun sequence bind the estrogen receptor in cell-free studies using a competitive band shift assay with the consensus element. The jun element also confers hormone inducibility to reporter plasmids in yeast and mammalian based transcriptional systems. Structure-function studies illustrate that the TGACC half-site and its immediate flanking dinucleotides, but not the GCAGA half-site, are required for estrogen receptor binding. In contrast, both the GCAGA and TGACC half-sites are obligatory for hormone-inducible transcriptional activation. These results suggest a model in which the estrogen receptor functions as a heterodimer to regulate transcription of the c- jun protooncogene. Coupled with reports of estrogen response elements in c- fos and estrogenic induction of c- fos and c- jun in vivo, these findings also support a role for AP-1 components as early response genes in estrogen-induced proliferation. The estrogen receptor (ER) 1The abbreviations used are:ERestrogen receptorHREhormone response elementEREestrogen response elementkbkilobase(s)CATchloramphenicol acetyltransferase. 1The abbreviations used are:ERestrogen receptorHREhormone response elementEREestrogen response elementkbkilobase(s)CATchloramphenicol acetyltransferase. belongs to a large family of related transcription factors that includes receptors for steroid hormones, vitamin D, thyroid hormone, retinoic acid, and many orphan receptors for which the ligands have not yet been identified (1Beato M. FASEB J. 1991; 5: 2044-2051Crossref PubMed Scopus (196) Google Scholar, 2Wahli W. Martinez E. FASEB J. 1991; 5: 2243-2249Crossref PubMed Scopus (254) Google Scholar). These receptors bind to specific nucleotide sequences in the DNA, known as hormone response elements or HREs. HREs are the sites of receptor binding to the regulatory regions of target genes, and these elements confer hormone inducibility to such genes. These elements generally act as enhancers in the sense that their influence on gene transcription is not strictly position- or orientation-dependent. estrogen receptor hormone response element estrogen response element kilobase(s) chloramphenicol acetyltransferase. estrogen receptor hormone response element estrogen response element kilobase(s) chloramphenicol acetyltransferase. The DNA response element for the estrogen receptor is known as the estrogen response element or ERE. The consensus ERE, which is a perfect palindrome with the sequence GGTCA nnnTGACC, was initially discovered in the chicken (3Burch J.B.E. Evans M.I. Friedman T.M. O'Malley B.J. Mol. Biol. Rep. 1988; 8: 1123-1131Google Scholar) and Xenopus vitellogenin genes (4Klein-Hitpass L. Ryffel G.U. Heitlinger E. Cato A.C.B. Nucleic Acids Res. 1988; 16: 647-663Crossref PubMed Scopus (322) Google Scholar) and is thus often referred to as the vit-ERE as well as the consensus ERE. It is generally thought that the ER binds to the palindromic vit-ERE as a homodimer (5Kumar V. Chambon P. Cell. 1988; 55: 145-156Abstract Full Text PDF PubMed Scopus (954) Google Scholar). However, some recent data are more consistent with the estrogen receptor binding as a monomer (6Gorski J. Furlow J.D. Murdoch F.E. Fritsch M. Kaneko K. Ying C. Malayer J.R. Biol. Reprod. 1993; 48: 8-14Crossref PubMed Scopus (52) Google Scholar), and it is clearly established that other members of the steroid/thyroid superfamily can function as heterodimers (7Hawa N.S. Hewison M. Farrow S.M. O'Riordan J.L.H. Endocrinology. 1994; 135: 1-3Crossref PubMed Scopus (1) Google Scholar). In addition to the vitellogenin ERE, a number of naturally occurring EREs have more recently been defined (8Anolik J.H. Klinge C.M. Bambara R.A. Hilf R. J. Steroid Biochem. Mol. Biol. 1993; 46: 713-730Crossref PubMed Scopus (28) Google Scholar), and most exhibit some sequence homology to the consensus element. However, there is considerable variability in these elements, and the vit-ERE is the only naturally occurring sequence so far identified that has two perfect palindromic half-sites. In contrast to the vit-ERE, few studies have directly investigated the nature of the estrogen receptor species that interacts with other EREs. Although the majority of HREs identified to date are located in the 5′-flanking region of target genes within 1-2 kb or less of the promoter (9Lannigan D.A. Koszewski N.J. Notides A.C. Mol. Cell. Endocrinol. 1993; 94: 47-54Crossref PubMed Scopus (5) Google Scholar), HREs have recently been found in the intron (10Sap J. deMagistris L. Stunnenberg H. Vennstrom B. EMBO J. 1990; 9: 887-896Crossref PubMed Scopus (86) Google Scholar) and 3′-untranslated regions (11Hyder S.M. Stancel G.M. Nawaz Z. McDonnell D.P. Loose-Mitchell D.S. J. Biol. Chem. 1992; 267: 18047-18054Abstract Full Text PDF PubMed Google Scholar, 12Langston A. Gudas L.J. Mech. Dev. 1992; 38: 217-228Crossref PubMed Scopus (235) Google Scholar) of hormone responsive genes. Thus, the location as well as the sequence of HREs for the steroid/thyroid receptor family may be more diverse than initially realized. We and others (13Herschman H.R. Annu. Rev. Biochem. 1991; 60: 281-319Crossref PubMed Scopus (942) Google Scholar, 14Hyder S.M. Stancel G.M. Loose-Mitchell D.S. Crit. Rev. Eukaryotic Gene Expr. 1994; 4: 55-116Crossref PubMed Scopus (36) Google Scholar) have investigated the role of the AP-1 family of transcription factors as early response genes mediating estrogen-induced proliferation as this group of regulatory factors mediates proliferative responses to many other mitogens. These studies have shown that estrogen and in in both c- fos D.S. C. Stancel G.M. Mol. Endocrinol. 1988; PubMed Scopus Google Scholar, A. Mol. Endocrinol. 1988; PubMed Google Scholar) and c- jun C. Loose-Mitchell D.S. L. Stancel G.M. J. Steroid Biochem. Mol. Biol. 1992; PubMed Scopus Google Scholar, A. Mol. Endocrinol. 1988; PubMed Scopus Google Scholar, Biochem. Res. 1990; PubMed Scopus Google Scholar) in the which in large transcriptional A. Mol. Endocrinol. 1988; PubMed Scopus Google Scholar, Biochem. Res. 1990; PubMed Scopus Google Scholar, Endocrinology. 1993; PubMed Scopus (28) Google Scholar, E. M. L. V. A. Biochem. Res. 1990; PubMed Scopus Google Scholar, L. C. B. M. V. A. J. Steroid Biochem. Mol. Biol. 1992; PubMed Scopus Google Scholar, L. C. B. M. V. A. J. Biochem. Mol. Biol. 1992; PubMed Scopus Google Scholar). We and others have identified EREs in both the (11Hyder S.M. Stancel G.M. Nawaz Z. McDonnell D.P. Loose-Mitchell D.S. J. Biol. Chem. 1992; 267: 18047-18054Abstract Full Text PDF PubMed Google Scholar, S.M. D.S. Gene 1991; PubMed Scopus Google Scholar) and A. R. Nucleic Acids Res. 1990; PubMed Scopus Google Scholar) c- fos genes, but a has not yet been identified in c- jun. We now report the of an enhancer within the coding sequence of the c- jun. The sequence in the c- jun with the consensus for estrogen receptor binding in cell-free band shift and confers hormone inducibility to in yeast and mammalian transcriptional assay systems. The of EREs in both AP-1 with their induction estrogen in the that AP-1 is a of the estrogen-induced which target proliferation. and was and was for yeast and other components was was for was as previously S.M. Stancel G.M. J. Steroid Biochem. Mol. Biol. 1994; 48: PubMed Scopus Google Scholar). was to a of and a in was to for the ER of was with in the or of for and the was with as previously S.M. J. Steroid Biochem. PubMed Scopus Google Scholar). ER generally to and not to was using the with as and generally to In some was used for the band shift and in others it was in for was in results or was used for shift shift the as as the of ER and DNA was with and was shift the S.M. Stancel G.M. J. Steroid Biochem. Mol. Biol. 1994; 48: PubMed Scopus Google Scholar). the binding of for of and of the vit-ERE or of the c- The generally of the as the of In some to of was used in to binding of receptor to gene c- jun The for addition of the and in most the was for a on the on in for containing binding with c- or in in the shift for which ER with vit-ERE only shift was a of for and the and The in the region of the ER J.D. H. J. Endocrinology. 1990; PubMed Scopus Google Scholar) of was used in the shift The oligodeoxynucleotides used for the for ER binding in the band shift the as shown in that a the with The the Xenopus vitellogenin gene was used as a for S.M. Stancel G.M. J. Steroid Biochem. Mol. Biol. 1994; 48: PubMed Scopus Google Scholar) and is referred to as the or vit-ERE the the used for is shown in S.M. Stancel G.M. J. Steroid Biochem. Mol. Biol. 1994; 48: PubMed Scopus Google and other using Fritsch J. Scholar). The of a number for ER have been previously D.P. Nawaz Z. C. J.H. O'Malley J. Steroid Biochem. Mol. Biol. 1991; PubMed Scopus Google Scholar). These yeast and reporter plasmids as The yeast reporter was L. PubMed Scopus Google Scholar) a two the of the the reporter containing the c- elements and the shown in and or the of the McDonnell D.P. O'Malley J. Biol. Chem. 1991; Full Text PDF PubMed Google Scholar). The number and of the oligodeoxynucleotides DNA the c- jun promoter in yeast for the of an ERE, the region to the of c- jun was the containing of the c- jun promoter R. K. Nucleic Acids Res. 1991; PubMed Scopus Google Scholar) with containing a The for have been previously S.M. C. 1994; Google Scholar). with the this was the of and the was for the of containing region of c- jun promoter was the with and the These also of mammalian the and the and B. Nucleic Acids Res. Scopus Google Scholar). and containing two of the sequence for The was used this C.M. 1994; Scholar). using the M. K. A. J. PubMed Google Scholar). cells with the and reporter plasmids in to yeast and This was used to a of The cells with cells an of and the of was as previously P. McDonnell D.P. O'Malley J. Biol. Chem. Full Text PDF PubMed Google Scholar). cells estrogen-induced D.A. Endocrinology. PubMed Scopus Google Scholar). in with studies cells on in to the was to containing to using the (11Hyder S.M. Stancel G.M. Nawaz Z. McDonnell D.P. Loose-Mitchell D.S. J. Biol. Chem. 1992; 267: 18047-18054Abstract Full Text PDF PubMed Google Scholar) with of the reporter of the ER J. O'Malley J. Biol. Chem. 1990; Full Text PDF PubMed Google Scholar), and of the to cells with and with for and for for the of and for induction of in the of with not with the in the the c- jun is induced in the in the of C. Loose-Mitchell D.S. L. Stancel G.M. J. Steroid Biochem. Mol. Biol. 1992; PubMed Scopus Google Scholar, A. L. E. M. Mol. Endocrinol. 1990; 4: PubMed Scopus Google Scholar), the gene is directly the transcriptional the of the ER and an ERE. an to for EREs we the region of the c- jun gene which has been for homology to the consensus element GGTCA nnnTGACC This includes kb of 5′-flanking the jun and kb of sequence as shown in the this region of DNA we which a homology with the in the two of the consensus element and perfect half-site or of the which during binding L. J.H. O'Malley Mol. Cell. Biol. 9: PubMed Scopus Google Scholar). We these to the naturally occurring EREs (8Anolik J.H. Klinge C.M. Bambara R.A. Hilf R. J. Steroid Biochem. Mol. Biol. 1993; 46: 713-730Crossref PubMed Scopus (28) Google Scholar). This identified in the 5′-flanking in the two in the and in of the gene as shown in the gene in for receptor we oligodeoxynucleotides containing the EREs in their naturally occurring for in binding these we a shift assay as previously S.M. Stancel G.M. J. Steroid Biochem. Mol. Biol. 1994; 48: PubMed Scopus Google Scholar, Z. Stancel G.M. McDonnell D.P. S.M. Mol. 1993; PubMed Scopus Google Scholar). This assay the of oligodeoxynucleotides to the binding of the ER to of consensus shown in we the of a number of the jun EREs to for ER binding. sequences in only the binding of ER to the consensus This GCAGA nnnTGACC, which is located in the of the gene as in perfect half-site but of the consensus sequence in the other half-site also shown in the vit-ERE and the c- fos (11Hyder S.M. Stancel G.M. Nawaz Z. McDonnell D.P. Loose-Mitchell D.S. J. Biol. Chem. 1992; 267: 18047-18054Abstract Full Text PDF PubMed Google Scholar), which used for both for ER binding as In addition to the studies shown in studies that and not for ER binding. Thus, of the jun EREs in only is to bind the ER as the competitive binding assay we shown in two specific of ER binding to the consensus sequence are In some other only specific band was not This is dependent the receptor of the of in S.M. Stancel G.M. J. Steroid Biochem. Mol. Biol. 1994; 48: PubMed Scopus Google Scholar). a band is with some receptor We have shown previously that the specific band in some is the ER to the ER S.M. Stancel G.M. J. Steroid Biochem. Mol. Biol. 1994; 48: PubMed Scopus Google Scholar), thus that the the hormone that for two both are also These not to a two are their a of not have with shift using receptor the Mol. Endocrinol. 1990; 4: PubMed Scopus Google Scholar), and species of ER may containing two sites J. M. C. R. W. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). for these studies both ER as the and both are with vit-ERE, or the The data in that the sequence which half-site identical to the consensus sequence with the vit-ERE for receptor binding. We that two other jun sequences and this identical half-site but to for ER thus that not sequences containing a perfect half-site for the binding of This that in the first half-site or flanking the TGACC in have a influence on the of the to bind the The of flanking this second half-site in is more in that of for ER binding to the vit-ERE is of both the and the oligodeoxynucleotides also for ER binding. In contrast, of the which is used as a for ER binding. these of we have also some for the band and of this is such as shown in can also be used to the binding of the ER to EREs on these results with a we to directly the binding of the with the However, we not a binding of this element with the ER using of binding assay S.M. Stancel G.M. J. Steroid Biochem. Mol. Biol. 1994; 48: PubMed Scopus Google Scholar). These of the receptor with the of the receptor with the to or the of the receptor to during the not These results that the of the ER for the sequence is to the in such binding the role of specific in the binding we a of oligodeoxynucleotides containing in the sites and flanking regions of the element. shown in these sequences in the GCAGA first half-site the TGACC second half-site of the GCAGA half-site in the region the two half sites and of the TGACC half-site These sequences used in the studies in The of on binding was to in the of the second half-site to to a of receptor binding as the of with However, in the first half-site of the element to as the sequence was to as as the element. to the GCAGA half-site on receptor binding. These results that the first half of the element has on receptor in the TGACC sequence binding. This that only the second half is in ER but this is with the that this TGACC in other regions of the gene and sequences in not to bind the receptor This that to the TGACC to the of ER binding to results in that the of two or to the TGACC half-site the of oligodeoxynucleotides to for ER binding. This that the TGACC and its immediate flanking are to confer the receptor binding in shift these findings in cell-free receptor binding ER it was of to the of jun sequences to confer hormone-inducible responses in systems. this we initially a transcriptional it levels of in the of results a of that the is of transcription of reporter in the or for many other the of the on induction of the reporter is are of inducibility the vit-ERE are also as a and as this element is a of reporter In addition we a containing the sequence as a in We previously that this sequence not confer hormone inducibility in mammalian cells (11Hyder S.M. Stancel G.M. Nawaz Z. McDonnell D.P. Loose-Mitchell D.S. J. Biol. Chem. 1992; 267: 18047-18054Abstract Full Text PDF PubMed Google Scholar) or in yeast Z. Stancel G.M. McDonnell D.P. S.M. Mol. 1993; PubMed Scopus Google Scholar) its of homology to the vit-ERE In a of we the of in the first or second half of the sequence on transcriptional the in the TGACC which receptor binding also hormone inducibility the in the first half-site which has on receptor binding an of hormone inducibility This that the first half of the sequence is for transcriptional but is not required for receptor binding This that the of a other than the ER the GCAGA region of the element is for the hormonal induction of transcriptional these findings in it was to the sequence was also as an in an mammalian We thus containing this element the as In estrogen a induction of in containing the not a induction of the in the or the containing or In the hormone to both Although these results in the yeast that the confers hormonal inducibility in mammalian c- jun is and induced in the of C. Loose-Mitchell D.S. L. Stancel G.M. J. Steroid Biochem. Mol. Biol. 1992; PubMed Scopus Google Scholar, Biochem. Res. 1990; PubMed Scopus Google Scholar, A. L. E. M. Mol. Endocrinol. 1990; 4: PubMed Scopus Google Scholar). L. C. B. M. V. A. J. Biochem. Mol. Biol. 1992; PubMed Scopus Google Scholar) and the of the induction to C. Loose-Mitchell D.S. L. Stancel G.M. J. Steroid Biochem. Mol. Biol. 1992; PubMed Scopus Google Scholar, A. L. E. M. Mol. Endocrinol. 1990; 4: PubMed Scopus Google Scholar) that jun induction is a primary hormonal response the of the ER with elements of the The of this was thus to c- jun a EREs in c- we initially the known nucleotide sequence of the gene K. Nucleic Acids Res. 1990; PubMed Scopus Google Scholar) for regions to the consensus vit-ERE, GGTCA this sequences identified and for ER binding with a competitive shift assay that EREs for their to the binding of the ER to the This is a it can elements with a of for the receptor S.M. Stancel G.M. J. Steroid Biochem. Mol. Biol. 1994; 48: PubMed Scopus Google Scholar, Z. Stancel G.M. McDonnell D.P. S.M. Mol. 1993; PubMed Scopus Google Scholar). these EREs only the sequence GCAGA nnnTGACC in the of the gene was in this This sequence a perfect second half-site, but has the consensus in the first half site. This is to the c- fos previously identified which also perfect consensus half-site with in the second (11Hyder S.M. Stancel G.M. Nawaz Z. McDonnell D.P. Loose-Mitchell D.S. J. Biol. Chem. 1992; 267: 18047-18054Abstract Full Text PDF PubMed Google Scholar). the competitive binding we that the of the ER for the in is less than its for the fos S.M. Stancel G.M. J. Steroid Biochem. Mol. Biol. 1994; 48: PubMed Scopus Google Scholar) and less than that for the Although it may be it is to in this that in studies have shown that the for induction of c- jun mRNA in the is than the for c- fos induction C. Loose-Mitchell D.S. L. Stancel G.M. J. Steroid Biochem. Mol. Biol. 1992; PubMed Scopus Google Scholar). of the of the vit-ERE for the estrogen receptor are (6Gorski J. Furlow J.D. Murdoch F.E. Fritsch M. Kaneko K. Ying C. Malayer J.R. Biol. Reprod. 1993; 48: 8-14Crossref PubMed Scopus (52) Google Scholar) which in a of for the c- jun sequence in and for the c- fos ERE. that the estrogen receptor of cells has been F.E. D.A. Furlow J.D. J. 1990; PubMed Scopus Google Scholar), these are consistent with a role for these c- fos and c- jun EREs in estrogen-induced proliferation. it is to that these of are based on cell-free binding studies using of In vivo, the of DNA, regions of transcription other may have on This for the jun identified in this the required for binding and transcriptional suggest the of in receptor binding to this element more the ER binding to in cell-free studies has we initially used a well established yeast based transcriptional assay that has identified EREs in other genes Z. Stancel G.M. McDonnell D.P. S.M. Mol. 1993; PubMed Scopus Google and containing both and of the element reporter for other regulatory of the element in hormone This may suggest that the sequence interacts with other regulatory to the of c- jun. The results in also that the of transcriptional is of the of the the for an element to be a studies in an D.A. Endocrinology. PubMed Scopus Google Scholar), established that the c- jun also confers hormone inducibility in mammalian cells as well as This is in with a recent report that a number of EREs are in both the yeast and mammalian cells D.A. McDonnell D.P. Mol. Endocrinol. 1994; 8: PubMed Scopus Google Scholar). the receptor binding and transcriptional studies that the sequence located within the of the gene can function as an ERE. However, most EREs identified to date have been found of target gene (9Lannigan D.A. Koszewski N.J. Notides A.C. Mol. Cell. Endocrinol. 1993; 94: 47-54Crossref PubMed Scopus (5) Google Scholar). We thus investigated the 5′-flanking region of c- jun sequences with which not in that was based on homology to the consensus element. this we a yeast containing a of the 5′-flanking region of the c- jun gene as This was of in to in These findings not the of other EREs in the 5′-flanking region of c- jun. the element we identified in the is in other we the and the c- jun genes for The second half of the element and the two immediate flanking on are in the gene K. A. 1988; PubMed Scopus Google Scholar) and only in a flanking nucleotide in the gene K. P. M. A. 1988; PubMed Scopus Google Scholar). The of this sequence and the estrogenic of jun in target cells species a role for this element in the hormonal of this early response the for receptor binding and transcriptional of the GCAGA nnnTGACC sequence in in the TGACC receptor in the GCAGA half-site as well as to that half-site not to ER binding in This that the ER not bind to the sequence as a which is the generally to bind to the palindromic vit-ERE (5Kumar V. Chambon P. Cell. 1988; 55: 145-156Abstract Full Text PDF PubMed Scopus (954) Google Scholar). flanking the TGACC are for ER binding and in as recently for other hormone response not gene containing the consensus bind the receptor with M. M. Nucleic Acids Res. 1991; PubMed Scopus Google Scholar), and are in the the receptor is with estrogen (8Anolik J.H. Klinge C.M. Bambara R.A. Hilf R. J. Steroid Biochem. Mol. Biol. 1993; 46: 713-730Crossref PubMed Scopus (28) Google Scholar). with these results suggest that to receptor binding sequences have a on the binding than previously In we also the of in the on transcriptional activation. In contrast to the receptor binding in half of the GCAGA nnnTGACC sequence the of the element to confer estrogen to reporter This was a which that of nucleotide ER binding cell-free and transcriptional in The results of these for the receptor binding and transcriptional be in is that the binding of the ER to the sequence in cell-free not a role in c- jun induction in but the ER is to M. Chambon P. P. Cell. 1990; Full Text PDF PubMed Scopus Google Scholar) a consensus half-site This more both half-sites of the sequence for binding in cell-free and only was for hormonal are the in the there is for binding of the ER to a half-site to that in and hormonal inducibility only half-site than both half sites as with We the most of data is that the ER interacts with an to regulate estrogen induction of c- jun In this the ER binding the TGACC half-site with its flanking dinucleotides, and with the GCAGA This as the binding of a ER heterodimer to the GCAGA nnnTGACC or the ER and the other bind to the DNA and to a model is also in of recent studies that induction of c- jun in the a of A. Endocrinology. 1994; PubMed Scopus Google Scholar, M. Endocrinology. 1994; PubMed Scopus Google Scholar). estrogen receptors Endocrinology. 1993; PubMed Scopus Google Scholar), and responses in these of the L. E. Stancel G.M. Biol. Reprod. PubMed Scopus Google Scholar). However, estrogen in to a in c- jun in an in c- jun in cells and some and in most cells M. Endocrinology. 1994; PubMed Scopus Google Scholar). This of estrogen receptor and hormonal induction of c- jun in the that factors the ER are in the estrogenic of the in this hormone target of c- jun a of the ER and is an we have the of a We have known AP-1 components P. M. 1991; PubMed Scopus Google Scholar), and M. J. 1991; PubMed Scopus Google Scholar), for binding to their consensus DNA binding sequences and some to sequences in this region of but these results Although the that a ER jun is thus results in the that other factors or elements a role in the of c- jun In we have identified the sequence GCAGA nnnTGACC within the of c- jun that binds the ER and confers hormonal inducibility to reporter genes, of a hormone response element. this is the first of an within the coding sequence of an there is for such regulatory elements in the coding region of other genes Furlow J.D. J. Mol. Endocrinol. 1993; Google Scholar). Structure-function studies are most consistent with a model in which this element transcription with a heterodimer containing the ER and The of a in c- jun a role for AP-1 as an early of the estrogen-induced proliferative response in target such as the We are to and the of for the of the estrogen receptor used in this We and of for of and for shift We are to for the of estrogen receptor