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The functional versatility of CREM is determined by its modular structure
B M Laoide1, N S Foulkes, F Schlotter
1Laboratoire de Génétique Moléculaire des Eucaryotes du CNRS, U184 de l'INSERM, Faculté de Médecine, Strasbourg, France.
The EMBO Journal
|March 1, 1993
Summary
The cAMP-responsive element modulator (CREM) gene produces transcription activators and repressors through alternative splicing. New CREM isoforms were identified, revealing how exon shuffling generates proteins with diverse functional domains, impacting gene regulation.
Area of Science:
- Molecular Biology
- Gene Regulation
- Transcriptional Control
Background:
- The CREM gene (cAMP-responsive element modulator) is known to generate both activators and repressors of cAMP-induced transcription.
- Alternative splicing of the CREM gene leads to diverse protein isoforms with varying functions.
Purpose of the Study:
- To determine the exon structure of the CREM gene and identify novel isoforms.
- To investigate how alternative splicing and exon shuffling generate CREM proteins with different functional domains.
- To analyze the DNA binding efficiencies and heterodimerization properties of CREM isoforms with CREB.
Main Methods:
- Exon structure determination of the CREM gene.
- Identification and characterization of new CREM isoforms.
- In vivo and in vitro studies of CREM isoform heterodimerization with CREB.
- Analysis of protein domains responsible for transcriptional activation and repression.
Main Results:
- New CREM isoforms generated by exon shuffling were identified, leading to proteins with varied functional domains.
- CREM isoforms efficiently bind to cAMP-response elements (CREs) and heterodimerize with each other and with CREB in vivo.
- Differential splicing of DNA binding domains in CREM isoforms affects binding efficiencies; CREM alpha/CREB heterodimers show stronger binding than CREM beta/CREB heterodimers.
- A phosphorylation domain and a glutamine-rich domain are sufficient for transcriptional activation.
- A minimal CREM repressor, containing the b-Zip motif, effectively antagonizes cAMP-induced transcription.
Conclusions:
- Alternative splicing of the CREM gene generates diverse isoforms with distinct structural and functional characteristics, modulating cAMP-induced transcription.
- CREM isoforms exhibit differential DNA binding affinities and heterodimerization capabilities, influencing transcriptional outcomes.
- Phosphorylation of CREM may play a role in regulating its repressor function.