Cell‐specific inhibitory and stimulatory effects of Fos and Jun on transcription activation by nuclear receptors

We investigated the effect of c‐Fos and/or c‐Jun co‐expression on transcription activation by the progesterone (PR), glucocorticoid (GR) or androgen (AR) receptors using three different reporter genes and four different cell lines. We found that c‐Fos could only inhibit, while c‐Jun could either inhibit or further stimulate receptor‐induced transcription. All these effects were receptor, promoter, and cell type specific, and, importantly, the steroid receptors had non‐reciprocal effects on the transactivation ability of c‐Jun in the presence or absence of c‐Fos. Collectively, these results argue against heterodimer formation as a mechanism to explain the phenomena. Transactivation by the endogenous PR in T47D cells could be inhibited by increasing the intracellular c‐Fos level with forskolin as well as by co‐expressing c‐Fos; no such effect was seen in MCF‐7 cells. The inhibition by c‐Fos of PR‐induced transcription involves a competitive mechanism, which requires the presence of the intact c‐Fos leucine zipper and is directed mainly at the transcription activation function (TAF) located in the PR and GR hormone binding domains (TAF‐2). However, the co‐expression of c‐Fos did not alter the ‘squelching/transcriptional interference’ by the PR of estrogen receptor (ER)‐induced transcription. Multiple mechanisms are discussed which may be involved in the crosstalk between the two signal transduction pathways.