DOWN-REGULATION OF HUMAN ALPHA-FETOPROTEIN PROMOTER BY C-JUN AND C-FOS

Effects of jun and fos genes on expression of the human alpha-fetoprot ein (AFP) gene was studied by transfecting a jun or fos expression pla smid into HuH-7 human hepatoma cells with the chloramphenicol acetyltr ansferase (CAT) gene linked to the human AFP 5'-flanking sequence. All members of the jun and fos gene families suppressed CAT expression. A mong the jun gene family, c-jun suppressed CAT expression most strongl y, followed by junB and junD. The fos gene family, on the other hand, showed much weaker suppression, with c-fos exhibiting the strongest ef fect. Mutagenesis experiments showed that transcriptional suppression by jun and fos was mediated by the AFP promoter region from -160 to -1 54 which is adjacent to the consensus of the glucocorticoid responsive element. Dexamethasone stimulated AFP promoter activity and this stim ulation was effectively counteracted by c-jun. These results show anta gonism between jun/fos and the glucocorticoid receptor on transcriptio nal regulation of the human AFP gene by either direct competition for DNA binding or protein-protein interaction.