cAMP responsive element modulator: a critical regulator of cytokine production.
paper
Cited
Public
- Authors
- Rauen, Thomas; Hedrich, Christian M; Tenbrock, Klaus; Tsokos, George C
- Year
- 2013
- Journal
- Trends in molecular medicine
- PMID
- 23491535
- DOI
- 10.1016/j.molmed.2013.02.001
- PMCID
- PMC3891595
T lymphocytes from patients with systemic lupus erythematosus (SLE) display a complex array of cellular, molecular, and signaling anomalies, many of which have been attributed to increased expression of the transcriptional regulator cAMP responsive element modulator α (CREMα). Recent evidence indicates that CREMα, in addition to its regulatory functions on gene promoters in T lymphocytes, alters the epigenetic conformation of cytokine genes by interacting with enzymes that control histone methylation and acetylation as well as cytosine-phosphate-guanosine (CpG) DNA methylation. This review summarizes the most recent findings on CREM protein expression in various cell types, in particular its effects on T lymphocyte biology in the context of both health and SLE. We emphasize CREMα as a key molecule that drives autoimmunity.
(A) Schematic of the human CREM gene sequence and promoters. The upper graph displays the genomic structure of the human CREM gene comprising 14 exons. The fourth and fifth exons (light green θ1 and θ2) are preferentially expressed in testicular CREM isoforms, although the functions are not yet known. Exons six and nine (orange τ1 and τ2) are supposed to be trans-activating glutamine-rich domains. The red exons, seven and eight, encode the kinase-inducible P box domains I and II. The light and dark gray exons encode DNA binding domains (DBD) 1 and 2. Below is an amplified section of the three 5′ exons with CREM promoters P1 (in front of the first exon) and P2 (between the first and the second exon). P1 is mainly controlled by specificity protein (SP)-1 which is activated through de-phosphorylation exerted by protein phosphatase (PP)-2A, whereas P2 is trans-regulated by transcription factors of the AP-1 protein family (c-jun/c-fos homo- and heterodimers) [34,38]. (B) Schematic of selected CREM isoforms. A large number of CREM/ICER isoforms is generated by the usage of different promoters, transcription factor activities, and alternative splicing mechanisms [18,27,31].
The effects of CREMα on IL2 and IL17 gene transcription. Abbreviations: HDAC1, histone deacetylase 1; DNMT-3a, DNA methyl transferase-3a; CpG, cytosine-phosphate-guanosine.
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|---|---|---|
| Ventral striatal regulation of CREM mediates impulsive action and drug addiction vulnerability. | 2018 | 28439100 |
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