cAMP responsive element modulator

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RefSeq (mRNA)



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cAMP responsive element modulator is a protein that in humans is encoded by the CREM gene,[1][2][3] and it belongs to the cAMP-responsive element binding protein family. It has multiple isoforms, which act either as repressors or activators.[4] CREB family is important for in regulating transcription in response to various stresses, metabolic and developmental signals.[5] CREM transcription factors also play an important role in many physiological systems, such as cardiac function,[6] circadian rhythms,[7] locomotion and spermatogenesis.[8]


This gene encodes a bZIP transcription factor that binds to the cAMP responsive element found in many viral and cellular promoters. It is an important component of cAMP-mediated signal transduction during the spermatogenetic cycle, as well as other complex processes. Alternative promoter and translation initiation site usage allows this gene to exert spatial and temporal specificity to cAMP responsiveness. Multiple alternatively spliced transcript variants encoding several different isoforms have been found for this gene, with some of them functioning as activators and some as repressors of transcriptnhunion.[3]

Gene location

The chromosomal location of CREM gene is 10p11.21, and it starts at 35415769 and ends at 35501886 bp from pter ( according to hg19-Feb_2009)[9]


CAMP responsive element modulator has been shown to interact with FHL5.[10][11]

Disease relevance of CREM

Panic disorder

One study reported the DNA sequence variations in the gene for CREM in panic disorder patients. It showed a significant excess of the shorter eight-repeat allele and of genotypes containing the eight-repeat allele in panic disorder patients.[12] The observed associations were limited to panic disorder without agoraphobia, and they were more prominent in females. But, the independent Italian and Spanish samples in this study did not support their results. Another family-based study showed little evidence of any susceptibility locus for panic disorder either within the CREM gene or in a nearby region on chromosome 10p11[13]

Spermiogenesis deficiency

Like Dr. Paolo Sassone-Corsi wrote in this article CREM is “a master-switch regulator in testis”.[14] It plays an important role in the regulation of the expression of post-meiotic genes, and this has been supported by several studies using CREM-mutation mice.[15] The results showed the first step in the process of sperm formation would be blocked if the germ cell development in mice CREM gene were disrupted. The cAMP response element sites can be found in the promoter region of some postmeiotic genes, so that the CREM can target and regulate these genes.[14]

Two studies proved that treat the rats with Salvia hypoleuca and Alpina galanga can significantly increased the CREM gene expression.[16][17]

Systemic lupus erythematousus

Less IL-2 will be produced from T cells in humans or mice with systemic lupus erythematousus (SLE). Some studies showed that an increased level CREM was presented in the nucleus of T lymphocytes from SLE patients. The CREM bound to the -180 site of the IL-2 promoter to repress its transcription.[18]


  1. Meyer TE, Habener JF (Nov 1992). "Cyclic AMP response element binding protein CREB and modulator protein CREM are products of distinct genes". Nucleic Acids Research. 20 (22): 6106. doi:10.1093/nar/20.22.6106. PMC 334485. PMID 1461747.
  2. Masquilier D, Foulkes NS, Mattei MG, Sassone-Corsi P (Nov 1993). "Human CREM gene: evolutionary conservation, chromosomal localization, and inducibility of the transcript". Cell Growth & Differentiation. 4 (11): 931–7. PMID 7916662.
  3. 3.0 3.1 "Entrez Gene: CREM cAMP responsive element modulator".
  4. Foulkes, N. S.; Sassone-Corsi, P. (1992-02-07). "More is better: activators and repressors from the same gene". Cell. 68 (3): 411–414. doi:10.1016/0092-8674(92)90178-f. ISSN 0092-8674. PMID 1739963.
  5. Sassone-Corsi, P. (1995-01-01). "Transcription factors responsive to cAMP". Annual Review of Cell and Developmental Biology. 11: 355–377. doi:10.1146/annurev.cb.11.110195.002035. ISSN 1081-0706. PMID 8689562.
  6. Isoda, Takayoshi; Paolocci, Nazareno; Haghighi, Kobra; Wang, Congrong; Wang, Yibin; Georgakopoulos, Dimitrios; Servillo, Giuseppe; Della Fazia, Maria Agnese; Kranias, Evangelia G. (2003-02-01). "Novel regulation of cardiac force-frequency relation by CREM (cAMP response element modulator)". FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 17 (2): 144–151. doi:10.1096/fj.01-0981com. ISSN 1530-6860. PMID 12554693.
  7. Sassone-Corsi, P. (2000-06-01). "CREM: a master-switch regulating the balance between differentiation and apoptosis in male germ cells". Molecular Reproduction and Development. 56 (2 Suppl): 228–229. doi:10.1002/(SICI)1098-2795(200006)56:2+<228::AID-MRD2>3.0.CO;2-B. ISSN 1040-452X. PMID 10824972.
  8. Sassone-Corsi, P. (1998-08-01). "CREM: a master-switch governing male germ cells differentiation and apoptosis". Seminars in Cell & Developmental Biology. 9 (4): 475–482. doi:10.1006/scdb.1998.0200. ISSN 1084-9521. PMID 9813195.
  9. "CREM (cAMP responsive element modulator)". Retrieved 2016-10-16.
  10. Fimia GM, De Cesare D, Sassone-Corsi P (Nov 2000). "A family of LIM-only transcriptional coactivators: tissue-specific expression and selective activation of CREB and CREM". Molecular and Cellular Biology. 20 (22): 8613–22. doi:10.1128/MCB.20.22.8613-8622.2000. PMC 102166. PMID 11046156.
  11. Fimia GM, De Cesare D, Sassone-Corsi P (Mar 1999). "CBP-independent activation of CREM and CREB by the LIM-only protein ACT". Nature. 398 (6723): 165–9. doi:10.1038/18237. PMID 10086359.
  12. Domschke, K.; Kuhlenbäumer, G.; Schirmacher, A.; Lorenzi, C.; Armengol, L.; DiBella, D.; Gratacos, M.; Garritsen, H. S.; Nöthen, M. M. (2003-02-01). "Human nuclear transcription factor gene CREM: genomic organization, mutation screening, and association analysis in panic disorder". American Journal of Medical Genetics Part B. 117B (1): 70–78. doi:10.1002/ajmg.b.10018. ISSN 1552-4841. PMID 12555239.
  13. Hamilton, Steven P.; Slager, Susan L.; Mayo, David; Heiman, Gary A.; Klein, Donald F.; Hodge, Susan E.; Fyer, Abby J.; Weissman, Myrna M.; Knowles, James A. (2004-04-01). "Investigation of polymorphisms in the CREM gene in panic disorder". American Journal of Medical Genetics Part B. 126B (1): 111–115. doi:10.1002/ajmg.b.20121. ISSN 1552-4841. PMID 15048659.
  14. 14.0 14.1 Krausz, Csilla; Sassone-Corsi, Paolo (2005-01-01). "Genetic control of spermiogenesis: insights from the CREM gene and implications for human infertility". Reproductive BioMedicine Online. 10 (1): 64–71. doi:10.1016/S1472-6483(10)60805-X.
  15. Nantel, F.; Monaco, L.; Foulkes, N. S.; Masquilier, D.; LeMeur, M.; Henriksén, K.; Dierich, A.; Parvinen, M.; Sassone-Corsi, P. (1996-03-14). "Spermiogenesis deficiency and germ-cell apoptosis in CREM-mutant mice". Nature. 380 (6570): 159–162. doi:10.1038/380159a0. ISSN 0028-0836. PMID 8600390.
  16. Jasem, Estakhr; Nasim, Javdan; Gholamreza, Motalleb; Naser, Sanchooli; Nader, Marzban; Maryam, Shams Lahijani; Abbas, Nikravesh; Vahid, Rostamian (2010-10-01). "Evaluation of the effects of Salvia hypoleuca on the cAMP-responsive element modulator (CREM) gene expression and spermatogenesis in rat". Middle East Fertility Society Journal. 15 (4): 274–277. doi:10.1016/j.mefs.2010.08.002.
  17. Mazaheri, Mahta; Shahdadi, Vahid; Nazari Boron, Ashraf (2016-10-16). "Molecullar and biochemical effect of alcohlic extract of Alpinia galanga on rat spermatogenesis process". Iranian Journal of Reproductive Medicine. 12 (11): 765–770. ISSN 1680-6433. PMC 4330656. PMID 25709632.
  18. Juang, Yuang-Taung; Wang, Ying; Solomou, Elena E.; Li, Yansong; Mawrin, Christian; Tenbrock, Klaus; Kyttaris, Vasileios C.; Tsokos, George C. (2005-04-01). "Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV". Journal of Clinical Investigation. 115 (4): 996–1005. doi:10.1172/JCI22854. ISSN 0021-9738. PMC 1070410. PMID 15841182.

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.