C-JUN REPRESSES TRANSCRIPTION OF THE HUMAN CHORIONIC-GONADOTROPIN ALPHA-GENES AND BETA-GENES THROUGH DISTINCT TYPES OF CRES

Chorionic gonadotropin (CG) is a heterodimeric placental hormone encod ed by separate alpha and beta subunit genes that is essential for the maintenance of pregnancy. The production of CG is stimulated by DNA sy nthesis inhibitors and by cAMP. The present study demonstrates that th e proto-oncogene c-jun represses transcription of the human CG alpha a nd CG beta promoters. c-Jun repressed the CG alpha promoter through a canonical cAMP response element (CRE) that is known to bind c-Jun and other members of the B-Zip transcription factor family. In the CG beta promoter, two adjacent sites, CRE1 (-299 to -289) and CRE2 (-240 to - 219), conveyed cAMP responsiveness via sequences that are distinct fro m the canonical element, TGACGTCA. Mutations within CG beta CRE1 or CR E2 reduced or abolished, respectively, c-jun-mediated repression. Alth ough the CG beta CREs do not contain consensus sequences previously de scribed to bind c-Jun, CRE2 bound c-Jun and c-Fos in electrophoretic m obility shift assays. Supershift assays, using anti-JUN antibody, demo nstrated that Jun formed part of the native complex that binds the CRE 2 in JEG-3 cells. A series of c-Jun mutants were used to analyze the t ranscription factor domains required for repression of the CG subunit promoters. The DNA binding and leucine zipper domains of c-Jun as web as the amino terminus, were required for repression of both subunit pr omoters. Thus, both the CG alpha and CG beta genes are repressed by c- Jun through promoter regions that convey cAMP-induced transcription, a lthough these DNA sequences are unrelated.