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

Abstract

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.

Integration of the Non-genomic and Genomic Actions of Estrogen

“…These included the fos, myc, and jun genes previously known to be stimulated by estrogen (15,26,27), which thereby validate our results. Here we extend the findings and implicate PI3K action in protooncogene up-regulation by E 2 .…”

Estrogen-induced proliferation of normal endometrial glandular cells is initiated by transcriptional activation of cyclin D1 via binding of c-Jun to an AP-1 sequence

“…Screening of the cyclin D1 promoter revealed that it lacks an estrogenresponse element (ERE), but contains an AP-1-binding site sequence located at À953 to À947 (Motokura and Arnold, 1993). Promoters of Jun and Fos are known to have functional EREs (Weisz and Rosales, 1990;Hyder et al, 1995), and expressions of c-Jun and c-Fos have reportedly been induced by estrogen in animal models (Webb et al, 1993). Our immunohistochemical analysis in human endometrial tissues revealed that expressions of c-Jun in the glandular cells was observed only in the proliferative phase (Figures 1c and d), but c-Fos expression was observed in both the proliferative and secretory phases.…”

Changing colors in mice: an inducible system that delivers: Figure 1.

“…Although this system has been reported to achieve a 100-fold induction of gene expression in vitro, a disadvantage of using estrogen-based systems is that endogenous genes containing sequence elements similar to the consensus estrogen response element may also be modulated in response to estrogen treatment. For example the c-jun promoter contains such a sequence, suggesting a transcriptional mechanism for the increased c-jun mRNA levels found in cells during hormone-induced proliferation (Hyder et al 1995). Other endogenous genes have also been reported to contain estrogen-regulated sequences (Hyder et al 2000).…”