INDUCIBILITY AND NEGATIVE AUTOREGULATION OF CREM - AN ALTERNATIVE PROMOTER DIRECTS THE EXPRESSION OF ICER, AN EARLY RESPONSE REPRESSOR

cAMP-responsive element modulator (CREM) expression is tissue specific and developmentally regulated. Here we report that CREM is unique wit hin the family of cAMP-responsive promoter element (CRE)-binding facto rs since it is inducible by activation of the cAMP signaling pathway. The kinetic of expression is characteristic of an early response gene. The induction is transient and cell specific, does not involve increa sed transcript stability, and does not require protein synthesis. Sign ificantly, the subsequent decline in CREM expression requires de novo protein synthesis. The induced transcript encodes a novel repressor, i nducible cAMP early repressor (ICER), and is generated from an alterna tive intronic promoter. A cluster of four CREs in this promoter direct s cAMP inducibility. ICER binds to these elements and thereby represse s the activity of its own promoter, thus constituting a negative autor egulatory loop.