Inducibility and negative autoregulation of CREM: An alternative promoter directs the expression of ICER, an early response repressor

Abstract

cAMP-responsive element modulator (CREM) expression is tissue specific and developmentally regulated. Here we report that CREM is unique within the family of cAMP-responsive promoter element (CRE)-binding factors 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 increased transcript stability, and does not require protein synthesis. Significantly, the subsequent decline in CREM expression requires de novo protein synthesis. The induced transcript encodes a novel repressor, inducible cAMP early repressor (ICER), and is generated from an alternative intronic promoter. A cluster of four CREs in this promoter directs cAMP inducibility. ICER binds to these elements and thereby represses the activity of its own promoter, thus constituting a negative autoregulatory loop.

Cross-talk in signal transduction: Ras-dependent induction of cAMP-responsive transcriptional repressor ICER by nerve growth factor

“…The products of the ICER transcripts is a group of proteins of approximately 13 ± 14 kD, which are generated from di erent splicing isoforms (Stehle et al, 1993;Molina et al, 1993). Western blot analyses with protein extracts prepared from control and NGF-treated PC12 cells were performed using an anti-ICER antibody.…”

“…The P2 intronic promoter, which directs ICER transcription, contains a cluster of four CRE-like elements see Figure 3a). These sites are termed CAREs (for cAMP autoregulatory responsive elements; Molina et al, 1993) and were demonstrated to be responsible for cAMP inducibility and to be the targets of ICER negative autoregulation. PC12 cells were transfected with various reporter constructs containing di erent ICER promoter fragments.…”

“…The CREM gene, because of its modular structure, also generates antagonists of cAMP-induced transcription (Foulkes et al, 1991a;Delmas et al, 1992;Stehle et al, 1993;Molina et al, 1993). In particular, an alternative promoter (P2) which lies within an intron near the 3' end of the CREM gene (Stehle et al, 1993;Molina et al, 1993), directs the transcription of a truncated product, termed ICER (Inducible cAMP Early Repressor). The ICER open reading frame corresponds to the C-terminal segment of the gene and generates a protein that, compared with the previously described CREM isoforms consists of only the bZip DNA bindingdimerization domain.…”

“…The ICER open reading frame corresponds to the C-terminal segment of the gene and generates a protein that, compared with the previously described CREM isoforms consists of only the bZip DNA bindingdimerization domain. The bZip domain directs speci®c ICER binding to a consensus CRE element (Stehle et al, 1993;Molina et al, 1993). ICER is able to heterodimerize with CREB and thus to function as a dominant repressor of cAMP-induced transcription.…”

The transcriptional repressor ICER and cAMP-induced programmed cell death

“…The CREM gene generates a family of activators and repressors by alternative splicing, translation initiation and use of an alternative intronic promoter (Delmas et al, 1992;Foulkes et al, 1992;Laoide et al, 1993;Molina et al, 1993). In order to determine the type of CREM transcripts which are induced in IPC-81 cells we used RNAse protection analysis (Figure 3a .…”