c-Fos dimerization with c-Jun represses c-Jun enhancement of androgen receptor transactivation

The transcriptional activity of the human androgen receptor (hAR), like other nuclear receptors, is dependent on accessory factors. One such factor is c-Jun, which has been shown to have a selective function of mediating androgen receptor-dependent transactivation. This c-Jun activity is inhibited by c-Fos, another protooncoprotein that can dimerize with c-Jun to form the transcription factor AP-1. Here we show that c-jun mediates hAR-induced transactivation from the promoter of the androgen-regulated gene, human kallikrein-2 (hKLK2), and c-Fos blocks this activity. Using c-Fos truncation mutants and measuring hKLK2-dependent transcription, we have determined that the bZIP region of c-Fos is required and sufficient for inhibiting c-Jun enhancement of hAR transactivation. Further truncation analysis of the bZIP shows that the c-Fos dimerization function, mediated through the leucine zipper, is essential for the negative activity, whereas DNA binding, mediated through the basic region, is dispensable. These results suggest that heterodimerization by c-Fos with c-Jun blocks c-Jun's ability to enhance hAR-induced transactivation.