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 GCAGAnnnTGACC which is identical to the consensus estrogen response element GGTCAnnnTGACC 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.