Inducible cAMP early repressor (ICER) splice variants are generated upon activation of an alternative, intronic promoter within the CREM gene. ICER is proposed to downregulate both its own expression, and the expression of other genes, containing cAMP-responsive promoter elements. To examine the biological function of the two ICER splice variants, I and IIgamma, in comparable cellular systems, we generated HEK 293 cell variants with controllable overexpression of either ICER I or IIgamma. These two splice variants contain two different variants of DNA binding domains. Overexpression of either ICER I or IIgamma strongly represses CRE-driven reportergene transcription but not AP1- or NFkappaB-driven transcription. Thus, high specificity is maintained even at ICER overexpression. We here show that both ICER I and IIgamma repress Pituitary adenylate cyclase-activating polypeptide (PACAP)-mediated c-fos mRNA induction with similar efficiency, indicating that both splice variants play an important role in modulating PACAP-mediated transcriptional activation of the c-fos gene. ICER I and IIgamma also repress cAMP-mediated activation of chromogranin A (CgA), indicating that these splice variants may function as negative feedback regulators in CgA synthesis. The proliferation rate was not altered in cells overexpressing ICER I or IIgamma. Thus, in the epithelial cells HEK 293, ICER I and IIgamma splice variants seem to exert similar biological function.
