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 ta rget cells during hormone induced proliferation, and this appears to b e a primary hormonal response involving transcriptional activation. In this report we have now identified an estrogen dependent enhancer wit hin the coding sequence of c-jun. This element has the sequence GCAGAn nnTGACC 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 s equence bind the estrogen receptor in cell-free studies using a compet itive band shift assay with the consensus element. The jun element als o confers hormone inducibility to re porter plasmids in yeast and mamm alian based transcriptional systems. Structure-function studies illust rate that the TGACC half-site and its immediate flanking dinucleotides , but not the GCAGA half-site, are required for estrogen receptor bind ing. In contrast, both the GCAGA and TGACC half-sites are obligatory f or 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 report s 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 co mponents as early response genes in estrogen-induced proliferation.