THE CYCLIC-AMP RESPONSE ELEMENTS OF THE GENES FOR ANGIOTENSIN-CONVERTING ENZYME AND PHOSPHOENOLPYRUVATE CARBOXYKINASE (GTP) CAN MEDIATE TRANSCRIPTIONAL ACTIVATION BY CREM-TAU AND CREM-ALPHA

The potential of the CREM family of proteins to activate transcription of the genes encoding the testis-specific isozyme of angiotensin conv erting enzyme (ACE(T)) and the gluconeogenic enzyme, phosphoenolpyruva te carboxykinase (GTP) (PEPCK) (EC 4.1.1.32) were investigated. Both C REM tau and CREM alpha bind efficiently to the putative cyclic AMP res ponse element (CRE) present in the ACE(T) gene (CRET) and to the CRE i n the PEPCK gene, In HepG2 cells, the CRE was required for the strong stimulation by CREM tau of the expression of a chimeric PEPCK (-210 to +73)-chloramphenicol acetyl transferase (CAT) gene, The CRE could be mutated to the CRET sequence without losing the stimulatory effects of CREM tau. However, a similar chimeric gene driven by the regulatory r egion of the ACE(T) gene, which contains the CRET site, could only be stimulated by CREM tau when its imperfect TATA element was mutated to an authentic TATA. Surprisingly, CREM alpha, an alleged inhibitor of C RE-mediated transcription, stimulated the expression of both PEPCK-CAT and ACE(T)-CAT genes in HepG2 cells, a process which required the pre sence of the CRE and the CRET sites, respectively, In contrast, when t he same CRE elements were used to drive the transcription of a chimeri c gene containing the thymidine kinase promoter linked to the CAT stru ctural gene, CREM alpha inhibited its expression in HepG2 and JEG3 cel ls, The expression of the same chimeric gene, however, was stimulated by CREM alpha in F9 embryonal carcinoma cells. These results demonstra ted that the nature of the transcriptional effects of CREM isoforms on CRE-mediated transcription depends on the specific gene, the specific cell type and the promoter context of the CRE site.