Other entities represented in this entry:
HGNC Approved Gene Symbol: CREM
Cytogenetic location: 10p11.21 Genomic coordinates (GRCh38): 10:35,126,846-35,212,958 (from NCBI)
CREM is a multiexonic gene that encodes both activators and antagonists of cAMP-inducible transcription by differential splicing. Splice variants with antagonistic function lack 2 glutamine-rich domains and block cAMP-induced transcription, whereas an isoform that includes these glutamine-rich domains is a transcriptional activator (Molina et al., 1993).
From a mouse pituitary cDNA library, Foulkes et al. (1991) isolated a protein highly homologous to nuclear factor CREB (123810), an activator of cAMP-responsive promoter elements (CREs). Unlike CREB, which is expressed uniformly in several cell types, the CREM gene showed cell-specific expression. Downstream of the stop codon was a second out-of-frame DNA-binding domain. Foulkes et al. (1991) identified 3 mRNA isoforms that appeared to be formed through differential cell-specific splicing. In contrast to CREB, CREM acts as a down-regulator of cAMP-induced transcription.
Masquilier et al. (1993) showed conservation of CREM sequences in the pig, chicken, lemur, and Xenopus. They cloned the full-length human CREM cDNA sequence and demonstrated that it has a high degree of identity with the mouse gene. They showed, furthermore, conservation of CREM cyclic AMP transcriptional inducibility in humans.
Molina et al. (1993) identified a splice variant of CREM that is induced by activation of the adenylyl cyclase signal transduction pathway. This isoform, which they called 'inducible cAMP early repressor' (ICER), is generated by induction of an internal promoter. Because ICER contains the DNA-binding domain without the transactivation domain of other CREM variants, it serves as a dominant-negative repressor of cAMP-induced transcription.
Using EMSA analysis, Solomou et al. (2001) showed that while stimulated T cells from normal individuals had increased binding of phosphorylated CREB to the -180 site of the interleukin-2 (IL2; 147680) promoter, nearly all stimulated T cells from systemic lupus erythematosus (SLE; 152700) patients had increased binding primarily of phosphorylated CREM at this site and to the transcriptional coactivators CREBBP (600140) and EP300 (602700). Increased expression of phosphorylated CREM correlated with decreased production of IL2. Solomou et al. (2001) concluded that transcriptional repression is responsible for the decreased production of IL2 and anergy in SLE T cells.
ACT (FHL5; 605126) is expressed exclusively in round spermatids, where it cooperates with transcriptional activator CREM in regulating various postmeiotic genes. Targeted inactivation of CREM leads to a complete block of mouse spermiogenesis. Macho et al. (2002) sought to identify the regulatory steps controlling the functional interplay between CREM and ACT. They found that ACT selectively associates with KIF17b (see 605037), a kinesin isoform highly expressed in male germ cells. The ACT-KIF17b interaction is restricted to specific stages of spermatogenesis and directly determines the intracellular localization of ACT. Sensitivity to leptomycin B indicates that KIF17b can be actively exported from the nucleus through the CRM1 receptor (602559). Thus, Macho et al. (2002) concluded that a kinesin directly controls the activity of a transcriptional coactivator by a tight regulation of its intracellular localization.
Tomita et al. (2003) examined the expression and effects of ICER in neonatal rat cardiac myocytes. They demonstrated that ICER is rapidly upregulated by stimulation of the beta-adrenergic receptor in cardiac myocytes and works as a negative regulator of hypertrophy as well as a positive mediator of apoptosis.
By in situ hybridization, Masquilier et al. (1993) demonstrated that the murine Crem gene is on chromosome 18; in the human, the gene was mapped by in situ hybridization to 10p12.1-p11.1 with a peak of distribution in the p11.2 band, and with a smaller secondary hybridization peak detected on 2q34.
Spermiogenesis is a complex process by which postmeiotic male germ cells differentiate into mature spermatozoa. This process involves remarkable structural and biochemical changes including nuclear DNA compaction and acrosome formation. The transcriptional activator CREM is highly expressed in postmeiotic cells and CREM may be responsible for the activation of several haploid germ cell-specific genes involved in the structuring of the spermatozoon. The specific role of CREM in spermiogenesis was addressed by Nantel et al. (1996) using CREM-deficient mice generated by homologous recombination. Analysis of the seminiferous epithelium in mutant male mice revealed postmeiotic arrest at the first step of spermiogenesis. Late spermatids were completely absent, and there was a significant increase in apoptotic germ cells. They showed that CREM deficiency results in the lack of postmeiotic cell-specific gene expression. The complete lack of spermatozoa in the mutant mice was reminiscent of cases of human infertility. About one-third of infertile men fall into the category of idiopathic infertility, i.e., they suffer from deficient spermatogenesis even though gonadotropic and androgenic hormone secretion are not subnormal.
Simultaneously and independently, Blendy et al. (1996) likewise observed severe impairment of spermatogenesis in mice in whom the CREM gene had been eliminated by gene targeting. Spermatids failed to differentiate into sperm and postmeiotic gene expression in the testis declined dramatically. The cessation of sperm development was not accompanied by decreases in the levels of follicle-stimulating hormone or testosterone.
Blendy, J. A., Kaestner, K. H., Weinbauer, G. F., Nieschlag, E., Schutz, G. Severe impairment of spermatogenesis in mice lacking the CREM gene. Nature 380: 162-165, 1996. [PubMed: 8600391] [Full Text: https://doi.org/10.1038/380162a0]
Foulkes, N. S., Borrelli, E., Sassone-Corsi, P. CREM gene: use of alternative DNA-binding domains generates multiple antagonists of cAMP-induced transcription. Cell 64: 739-749, 1991. [PubMed: 1847666] [Full Text: https://doi.org/10.1016/0092-8674(91)90503-q]
Macho, B., Brancorsini, S., Fimia, G. M., Setou, M., Hirokawa, N., Sassone-Corsi, P. CREM-dependent transcription in male germ cells controlled by a kinesin. Science 298: 2388-2390, 2002. [PubMed: 12493914] [Full Text: https://doi.org/10.1126/science.1077265]
Masquilier, D., Foulkes, N. S., Mattei, M.-G., Sassone-Corsi, P. Human CREM gene: evolutionary conservation, chromosomal localization, and inducibility of the transcript. Cell Growth Differ. 4: 931-937, 1993. [PubMed: 7916662]
Molina, C. A., Foulkes, N. S., Lalli, E., Sassone-Corsi, P. Inducibility and negative autoregulation of CREM: an alternative promoter directs the expression of ICER, an early response repressor. Cell 75: 875-886, 1993. [PubMed: 8252624] [Full Text: https://doi.org/10.1016/0092-8674(93)90532-u]
Nantel, F., Monaco, L., Foulkes, N. S., Masquilier, D., LeMeur, M., Henriksen, K., Dierich, A., Parvinen, M., Sassone-Corsi, P. Spermiogenesis deficiency and germ-cell apoptosis in CREM-mutant mice. Nature 380: 159-162, 1996. [PubMed: 8600390] [Full Text: https://doi.org/10.1038/380159a0]
Solomou, E. E., Juang, Y.-T., Gourley, M. F., Kammer, G. M., Tsokos, G. C. Molecular basis of deficient IL-2 production in T cells from patients with systemic lupus erythematosus. J. Immun. 166: 4216-4222, 2001. [PubMed: 11238674] [Full Text: https://doi.org/10.4049/jimmunol.166.6.4216]
Tomita, H., Nazmy, M., Kajimoto, K., Yehia, G., Molina, C. A., Sadoshima, J. Inducible cAMP early repressor (ICER) is a negative-feedback regulator of cardiac hypertrophy and an important mediator of cardiac myocyte apoptosis in response to beta-adrenergic receptor stimulation. Circ. Res. 93: 12-22, 2003. [PubMed: 12791704] [Full Text: https://doi.org/10.1161/01.RES.0000079794.57578.F1]