ESTROGEN REGULATION OF THE INSULIN-LIKE GROWTH-FACTOR-I GENE-TRANSCRIPTION INVOLVES AN AP-1 ENHANCER

As a step toward elucidating the physiological role of insulin-like gr owth factor-I (IGF-I) in mediating estrogen action, we sought to deter mine the molecular basis of the phenomenon. In HepG2 cells expressing exogenous estrogen receptors (ER), a reporter gene plasmid containing 600 base pairs of the chicken IGF-I promoter enhanced expression of lu ciferase 8.6-fold in response to 10(-6) M 17 beta-estradiol, indicatin g that the IGF-I promoter is a target of estrogen regulation. Although no conventional estrogen-responsive element was identified within the promoter fragment, the AP-1 motif located therein was shown to be ess ential; the estrogen-responsive enhancement of the Fos-Jun binding to the AP-1 motif, which takes place by means of post-translational modif ication, mediates the estrogen action. A direct or indirect interactio n between the estrogen-ER complex and the Fos-Jun complex seems to fac ilitate the Fos-Jun binding to the target DNA. Although ER binding to the target DNA was not considered to be involved in the signaling path way, the DNA binding domain-deficient ER did not mediate the phenomeno n, providing support for the existence of a unique function of the DNA binding domain of ER in facilitating some protein-protein interaction . In conclusion, our present observations demonstrate that the chicken IGF-I gene promoter is controlled by estrogen through a unique pathwa y involving Fos, Jun, and the DNA binding domain of ER.