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Gene Review

CREM  -  cAMP responsive element modulator

Homo sapiens

Synonyms: CREM-2, ICER, Inducible cAMP early repressor, cAMP-responsive element modulator, hCREM-2
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Disease relevance of CREM


Psychiatry related information on CREM


High impact information on CREM

  • Nuclear factor CRE modulator (CREM) is activated by PKA-mediated phosphorylation on a serine at position 117 [5].
  • The macrolide rapamycin, a potent and specific inhibitor of p70S6K in vivo, completely blocks CREM activation induced by serum and by p70S6K [5].
  • We demonstrate that while CREB is expressed uniformly in several cell types, this gene, termed CREM, shows cell-specific expression [6].
  • Using a two-hybrid screen, we have isolated a testis-derived complementary DNA encoding a protein that we term ACT (for activator of CREM in testis), a LIM-only protein which specifically associates with CREM [7].
  • The activator CREM is highly expressed in male germ cells and is required for post-meiotic gene expression [7].

Chemical compound and disease context of CREM

  • Here, we show that a direct protein-protein interaction between DREAM and the CREM repressor isoform, alphaCREM, prevents binding of DREAM to the DRE and suggests a mechanism for cyclic AMP-dependent derepression of the prodynorphin gene in human neuroblastoma cells [8].
  • In contrast, pretreatment with adenovirus overexpressing icer was effective in reducing the NE induction of mkp-1 and aa-nat [9].
  • The ICER of RT-GEM was most sensitive to utility values, and, at lower efficacy levels, to costs of gemcitabine and treatment-related toxicity [10].

Biological context of CREM


Anatomical context of CREM


Associations of CREM with chemical compounds

  • By in vitro transcription/translation of all six CREM cDNAs, we demonstrated internal translation initiation at three different methionine residues, giving rise to novel short and very short C-terminal proteins comprising DBD I [17].
  • By using the CREM-deficient mice and by analysis of the regulatory region of the gene encoding the serotonin NAT, we have established that ICER is responsible for the amplitude and rhythmicity of NAT and thus for the oscillation in the hormonal synthesis of melatonin [18].
  • The CREM (cyclic AMP-responsive element modulator) gene encodes multiple regulators of the cyclic AMP transcriptional response [19].
  • In addition, phosphorylation may reduce repressor function, as a CREM beta mutant carrying a mutation of the serine phosphoacceptor site (CREM beta 68) represses more efficiently than the wild-type CREM beta [20].
  • Expression of CREM delta C-G inhibits transcription of a CRE-containing chloramphenicol acetyltransferase reporter plasmid induced by endogenous CREB [21].

Physical interactions of CREM

  • These results suggest that the activation of the insulin gene transcription by CREM activator is mediated by not only direct binding to the CREs but also by recruiting transcription factor IID to the insulin promoter via its interaction with hTAF(II)130 and TBP [22].
  • Ca(2+)/calmodulin-dependent kinase IV (CaMKIV) was found to be increased in the nucleus of SLE T cells and to be involved in the overexpression of CREM and its binding to the IL-2 promoter [23].
  • In this study, we demonstrate that CREM binds to the proximal promoter of the c-fos proto-oncogene in live systemic lupus erythematosus T cells and represses its expression following stimulation in vitro [24].
  • We show that ICER binds specifically to several NFAT/AP-1 (nuclear factor of activated T cells/activating protein-1) composite DNA sites essential for the activation of the interleukin (IL)-2 promoter as well as to a homologous DNA motif present in the proximal segment of the interferon-gamma promoter [25].

Regulatory relationships of CREM

  • Antisense CREM also enhanced the accessibility of the IL-2 promoter to endonucleases and prevented the condensation of chromatin in vivo [1].
  • We used one of these functional sequences to screen a lambda gt11 cDNA expression library resulting in the isolation of cDNA clones encoding the transcription factors ATF-1 (activating transcription factor) and CREM (cyclic AMP response element modulator) [26].
  • We conclude that CREM represses the expression of c-fos and limits the activity of the enhancer AP-1 [24].
  • T cells from patients with systemic lupus erythematosus express increased levels of the cAMP response element modulator (CREM) that has been shown to bind to the IL-2 promoter and suppress its activity [24].
  • Here, we demonstrate that ICER induction repressed PDE3A gene transcription [27].

Other interactions of CREM

  • Consistent with these results, the endogenous ICER protein is elevated in cells which are null for murine Rad6B (mHR6B-/-) or transfected with dominant negative and antisense constructs of human CDC34 [28].
  • High amounts of CREM proteins were present in H295R, demonstrating an overexpression of this transcription factor in the absence of CREB [29].
  • This shows that in a eukaryotic nucleus, Tax specifically interacts with the basic domain-leucine zipper region of ATF-1, CREB, and CREM [30].
  • Antibodies to cAMP response element modulator (CREM) and proliferating nuclear cell antigen (PCNA) and a cRNA directed against protamine P2 and morphological criteria were used to discriminate between stages of the spermatogenic cycle [31].
  • CKLiK kinase activity was dependent on Ca(++) and calmodulin as analyzed by in vitro phosphorylation of cyclic adenosine monophosphate responsive element modulator (CREM) [32].

Analytical, diagnostic and therapeutic context of CREM

  • Immunofluorescence showed nuclear localization of C-terminal CREM proteins expressed from all six CREM cDNAs [17].
  • By using electrophoretic mobility-shift assays, we demonstrated that both nuclear protein extract from highly purified rat spermatid cells and recombinant CREM-tau protein can specifically bind to this element [16].
  • Preliminary sequence analysis of the region located upstream of the alternative exon revealed some potential DNA-binding sites, one of which is specific to the binding of CREM (cAMP-response element modulator) transcription factors [16].
  • We have used gene targeting to selectively eliminate the transcription factor CREM (cyclic AMP- responsive element modulator), which is thought to be important for mammalian spermatogenesis [3].
  • An important role of CREM in liver physiology was suggested by the robust induction of ICER after partial hepatectomy [33].


  1. The cyclic adenosine 5'-monophosphate response element modulator suppresses IL-2 production in stimulated T cells by a chromatin-dependent mechanism. Tenbrock, K., Juang, Y.T., Tolnay, M., Tsokos, G.C. J. Immunol. (2003) [Pubmed]
  2. Variable expression of the transcription factors cAMP response element-binding protein and inducible cAMP early repressor in the normal adrenal cortex and in adrenocortical adenomas and carcinomas. Peri, A., Luciani, P., Conforti, B., Baglioni-Peri, S., Cioppi, F., Crescioli, C., Ferruzzi, P., Gelmini, S., Arnaldi, G., Nesi, G., Serio, M., Mantero, F., Mannelli, M. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  3. Severe impairment of spermatogenesis in mice lacking the CREM gene. Blendy, J.A., Kaestner, K.H., Weinbauer, G.F., Nieschlag, E., Schütz, G. Nature (1996) [Pubmed]
  4. Investigation of polymorphisms in the CREM gene in panic disorder. Hamilton, S.P., Slager, S.L., Mayo, D., Heiman, G.A., Klein, D.F., Hodge, S.E., Fyer, A.J., Weissman, M.M., Knowles, J.A. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2004) [Pubmed]
  5. Positive regulation of the cAMP-responsive activator CREM by the p70 S6 kinase: an alternative route to mitogen-induced gene expression. de Groot, R.P., Ballou, L.M., Sassone-Corsi, P. Cell (1994) [Pubmed]
  6. CREM gene: use of alternative DNA-binding domains generates multiple antagonists of cAMP-induced transcription. Foulkes, N.S., Borrelli, E., Sassone-Corsi, P. Cell (1991) [Pubmed]
  7. CBP-independent activation of CREM and CREB by the LIM-only protein ACT. Fimia, G.M., De Cesare, D., Sassone-Corsi, P. Nature (1999) [Pubmed]
  8. DREAM-alphaCREM interaction via leucine-charged domains derepresses downstream regulatory element-dependent transcription. Ledo, F., Carrión, A.M., Link, W.A., Mellström, B., Naranjo, J.R. Mol. Cell. Biol. (2000) [Pubmed]
  9. The role of inducible repressor proteins in the adrenergic induction of arylalkylamine-N-acetyltransferase and mitogen-activated protein kinase phosphatase-1 in rat pinealocytes. Ho, A.K., Terriff, D.L., Price, D.M., Wloka, M.T., Chik, C.L. Endocrinology (2007) [Pubmed]
  10. Using economic analysis to evaluate the potential of multimodality therapy for elderly patients with locally advanced pancreatic cancer. Krzyzanowska, M.K., Earle, C.C., Kuntz, K.M., Weeks, J.C. Int. J. Radiat. Oncol. Biol. Phys. (2007) [Pubmed]
  11. Identification and expression of a novel isoform of cAMP response element modulator in the human heart. Müller, F.U., Bokník, P., Knapp, J., Neumann, J., Vahlensieck, U., Oetjen, E., Scheld, H.H., Schmitz, W. FASEB J. (1998) [Pubmed]
  12. Differential activation of viral and cellular promoters by human T-cell lymphotropic virus-1 tax and cAMP-responsive element modulator isoforms. Laurance, M.E., Kwok, R.P., Huang, M.S., Richards, J.P., Lundblad, J.R., Goodman, R.H. J. Biol. Chem. (1997) [Pubmed]
  13. The dynamics of the transcriptional response to cyclic adenosine 3',5'-monophosphate: recurrent inducibility and refractory phase. Lamas, M., Sassone-Corsi, P. Mol. Endocrinol. (1997) [Pubmed]
  14. The expanding family of CREB/CREM transcription factors that are involved with spermatogenesis. Don, J., Stelzer, G. Mol. Cell. Endocrinol. (2002) [Pubmed]
  15. Round spermatids show normal testis-specific H1t but reduced cAMP-responsive element modulator and transition protein 1 expression in men with round-spermatid maturation arrest. Steger, K., Klonisch, T., Gavenis, K., Behr, R., Schaller, V., Drabent, B., Doenecke, D., Nieschlag, E., Bergmann, M., Weinbauer, G.F. J. Androl. (1999) [Pubmed]
  16. cAMP-response element modulator-tau activates a distinct promoter element for the expression of the phospholipid hydroperoxide/sperm nucleus glutathione peroxidase gene. Tramer, F., Vetere, A., Martinelli, M., Paroni, F., Marsich, E., Boitani, C., Sandri, G., Panfili, E. Biochem. J. (2004) [Pubmed]
  17. Human endometrial stromal cells express novel isoforms of the transcriptional modulator CREM and up-regulate ICER in the course of decidualization. Gellersen, B., Kempf, R., Telgmann, R. Mol. Endocrinol. (1997) [Pubmed]
  18. Coupling signalling pathways to transcriptional control: nuclear factors responsive to cAMP. Tamai, K.T., Monaco, L., Nantel, F., Zazopoulos, E., Sassone-Corsi, P. Recent Prog. Horm. Res. (1997) [Pubmed]
  19. Human CREM gene: evolutionary conservation, chromosomal localization, and inducibility of the transcript. Masquilier, D., Foulkes, N.S., Mattei, M.G., Sassone-Corsi, P. Cell Growth Differ. (1993) [Pubmed]
  20. The functional versatility of CREM is determined by its modular structure. Laoide, B.M., Foulkes, N.S., Schlotter, F., Sassone-Corsi, P. EMBO J. (1993) [Pubmed]
  21. An isoform of transcription factor CREM expressed during spermatogenesis lacks the phosphorylation domain and represses cAMP-induced transcription. Walker, W.H., Sanborn, B.M., Habener, J.F. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  22. The cyclic AMP response element modulator family regulates the insulin gene transcription by interacting with transcription factor IID. Inada, A., Someya, Y., Yamada, Y., Ihara, Y., Kubota, A., Ban, N., Watanabe, R., Tsuda, K., Seino, Y. J. Biol. Chem. (1999) [Pubmed]
  23. Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV. Juang, Y.T., Wang, Y., Solomou, E.E., Li, Y., Mawrin, C., Tenbrock, K., Kyttaris, V.C., Tsokos, G.C. J. Clin. Invest. (2005) [Pubmed]
  24. Cyclic adenosine 5'-monophosphate response element modulator is responsible for the decreased expression of c-fos and activator protein-1 binding in T cells from patients with systemic lupus erythematosus. Kyttaris, V.C., Juang, Y.T., Tenbrock, K., Weinstein, A., Tsokos, G.C. J. Immunol. (2004) [Pubmed]
  25. Role of transcriptional repressor ICER in cyclic AMP-mediated attenuation of cytokine gene expression in human thymocytes. Bodor, J., Habener, J.F. J. Biol. Chem. (1998) [Pubmed]
  26. Activating transcription factor 1 and cyclic AMP response element modulator can modulate the activity of the immunoglobulin kappa 3' enhancer. Pongubala, J.M., Atchison, M.L. J. Biol. Chem. (1995) [Pubmed]
  27. A positive feedback loop of phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis. Ding, B., Abe, J., Wei, H., Xu, H., Che, W., Aizawa, T., Liu, W., Molina, C.A., Sadoshima, J., Blaxall, B.C., Berk, B.C., Yan, C. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  28. Human Cdc34 and Rad6B ubiquitin-conjugating enzymes target repressors of cyclic AMP-induced transcription for proteolysis. Pati, D., Meistrich, M.L., Plon, S.E. Mol. Cell. Biol. (1999) [Pubmed]
  29. Loss of expression of the ubiquitous transcription factor cAMP response element-binding protein (CREB) and compensatory overexpression of the activator CREMtau in the human adrenocortical cancer cell line H295R. Groussin, L., Massias, J.F., Bertagna, X., Bertherat, J. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
  30. Genetic characterization of transactivation of the human T-cell leukemia virus type 1 promoter: Binding of Tax to Tax-responsive element 1 is mediated by the cyclic AMP-responsive members of the CREB/ATF family of transcription factors. Bantignies, F., Rousset, R., Desbois, C., Jalinot, P. Mol. Cell. Biol. (1996) [Pubmed]
  31. Marmoset spermatogenesis: organizational similarities to the human. Millar, M.R., Sharpe, R.M., Weinbauer, G.F., Fraser, H.M., Saunders, P.T. Int. J. Androl. (2000) [Pubmed]
  32. Identification and characterization of CKLiK, a novel granulocyte Ca(++)/calmodulin-dependent kinase. Verploegen, S., Lammers, J.W., Koenderman, L., Coffer, P.J. Blood (2000) [Pubmed]
  33. Coupling cAMP signaling to transcription in the liver: pivotal role of CREB and CREM. Servillo, G., Della Fazia, M.A., Sassone-Corsi, P. Exp. Cell Res. (2002) [Pubmed]
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