FUNCTIONAL ANTAGONISM BETWEEN THE ESTROGEN-RECEPTOR AND FOS IN THE REGULATION OF C-FOS PROTOONCOGENE TRANSCRIPTION

Estrogen hormones induce transient transcriptional activation of c-fos during the early phases of mitogenic stimulation of target cells. Thi s is mediated by a functional estrogen response element (ERE) that in the human c-fos gene is localized 1kb up-stream of the transcription s tart site. This is the first known example of transient transcriptiona l activation induced by a steroid hormone acting via its nuclear recep tor. Starting with the hypothesis that the product of c-fos (Fos) inte rferes with estrogen receptor (ER) activity on this gene promoter, gen erating in this way a feedback inhibition mechanism responsible for th e rapid transcriptional down-regulation detected in vivo, we tested th e effects of Fos over-expression on ER-mediated activation of the c-fo s promoter in transfected HeLa cells. Transient transfection of an ER expression vector is followed by hormone-dependent trans-activation of reporter genes comprising the c-fos ERE linked to its own promoter. C oexpression of Fos in the cell induces a significant reduction in the activity of ER on the reporter genes. Fos antagonism is effective on b oth transcription activation functions of the receptor molecule and is independent of the nature of the target promoter. Furthermore, under the same experimental conditions, the estrogen-receptor complex antago nizes activation of an AP-1-responsive test gene by Fos. ER mutants de prived of the DNA-binding domain are efficient inhibitors of Fos activ ity, indicating that reciprocal antagonism is likely to be mediated by the formation of inactive complexes between the two factors. These re sults reveal the existence of a functional interference between the ER and Fos for regulation of c-fos protooncogene transcription. It is th e first case in which the product of an estrogen-induced growth-relate d gene is shown to exert a negative feedback control on ER regulation of its own promoter.