CAMP responsive element modulator explained

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]

Function

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 transcription.

Gene location

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

Interactions

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

CREM has been shown to be 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]

Further reading

• Don J, Stelzer G . The expanding family of CREB/CREM transcription factors that are involved with spermatogenesis . Molecular and Cellular Endocrinology . 187 . 1–2 . 115–124 . February 2002 . 11988318 . 10.1016/S0303-7207(01)00696-7 . 23023082 .
• Yan C, Miller CL, Abe J . Regulation of phosphodiesterase 3 and inducible cAMP early repressor in the heart . Circulation Research . 100 . 4 . 489–501 . March 2007 . 17332439 . 4115784 . 10.1161/01.RES.0000258451.44949.d7 .
• Pongubala JM, Atchison ML . Activating transcription factor 1 and cyclic AMP response element modulator can modulate the activity of the immunoglobulin kappa 3' enhancer . The Journal of Biological Chemistry . 270 . 17 . 10304–10313 . April 1995 . 7730336 . 10.1074/jbc.270.17.10304 . free .
• Walker WH, Sanborn BM, Habener JF . An isoform of transcription factor CREM expressed during spermatogenesis lacks the phosphorylation domain and represses cAMP-induced transcription . Proceedings of the National Academy of Sciences of the United States of America . 91 . 26 . 12423–12427 . December 1994 . 7809053 . 45450 . 10.1073/pnas.91.26.12423 . free . 1994PNAS...9112423W .
• Fujimoto T, Fujisawa J, Yoshida M . Novel isoforms of human cyclic AMP-responsive element modulator (hCREM) mRNA . Journal of Biochemistry . 115 . 2 . 298–303 . February 1994 . 8206879 . 10.1093/oxfordjournals.jbchem.a124332 .
• de Groot RP, den Hertog J, Vandenheede JR, Goris J, Sassone-Corsi P . Multiple and cooperative phosphorylation events regulate the CREM activator function . The EMBO Journal . 12 . 10 . 3903–3911 . October 1993 . 8404858 . 413673 . 10.1002/j.1460-2075.1993.tb06068.x .
• Bodor J, Walker W, Flemington E, Spetz AL, Habener JF . Modulation of Tax and PKA-mediated expression of HTLV-I promoter via cAMP response element binding and modulator proteins CREB and CREM . FEBS Letters . 377 . 3 . 413–418 . December 1995 . 8549766 . 10.1016/0014-5793(95)01299-0 . 45422227 . 1995FEBSL.377..413B .
• Nantel F, Monaco L, Foulkes NS, Masquilier D, LeMeur M, Henriksén K, Dierich A, Parvinen M, Sassone-Corsi P . Spermiogenesis deficiency and germ-cell apoptosis in CREM-mutant mice . Nature . 380 . 6570 . 159–162 . March 1996 . 8600390 . 10.1038/380159a0 . 4278745 . 1996Natur.380..159N .
• Blendy JA, Kaestner KH, Weinbauer GF, Nieschlag E, Schütz G . Severe impairment of spermatogenesis in mice lacking the CREM gene . Nature . 380 . 6570 . 162–165 . March 1996 . 8600391 . 10.1038/380162a0 . 4337719 . 1996Natur.380..162B .
• Bodor J, Spetz AL, Strominger JL, Habener JF . cAMP inducibility of transcriptional repressor ICER in developing and mature human T lymphocytes . Proceedings of the National Academy of Sciences of the United States of America . 93 . 8 . 3536–3541 . April 1996 . 8622971 . 39645 . 10.1073/pnas.93.8.3536 . free . 1996PNAS...93.3536B .
• Gellersen B, Kempf R, Telgmann R . Human endometrial stromal cells express novel isoforms of the transcriptional modulator CREM and up-regulate ICER in the course of decidualization . Molecular Endocrinology . 11 . 1 . 97–113 . January 1997 . 8994192 . 10.1210/mend.11.1.9875 . free .
• Laurance ME, Kwok RP, Huang MS, Richards JP, Lundblad JR, Goodman RH . Differential activation of viral and cellular promoters by human T-cell lymphotropic virus-1 tax and cAMP-responsive element modulator isoforms . The Journal of Biological Chemistry . 272 . 5 . 2646–2651 . January 1997 . 9006899 . 10.1074/jbc.272.5.2646 . free .
• Bonny C, Cooker LA, Goldberg E . Deoxyribonucleic acid-protein interactions and expression of the human testis-specific lactate dehydrogenase promoter: transcription factor Sp1 plays a major role . Biology of Reproduction . 58 . 3 . 754–759 . March 1998 . 9510963 . 10.1095/biolreprod58.3.754 . free .
• Müller FU, Bokník P, Knapp J, Neumann J, Vahlensieck U, Oetjen E, Scheld HH, Schmitz W . Identification and expression of a novel isoform of cAMP response element modulator in the human heart . FASEB Journal . 12 . 12 . 1191–1199 . September 1998 . 9737722 . 10.1096/fasebj.12.12.1191 . 34554530 . free .
• Fimia GM, De Cesare D, Sassone-Corsi P . CBP-independent activation of CREM and CREB by the LIM-only protein ACT . Nature . 398 . 6723 . 165–169 . March 1999 . 10086359 . 10.1038/18237 . 4424908 . 1999Natur.398..165F .
• Pati D, Meistrich ML, Plon SE . Human Cdc34 and Rad6B ubiquitin-conjugating enzymes target repressors of cyclic AMP-induced transcription for proteolysis . Molecular and Cellular Biology . 19 . 7 . 5001–5013 . July 1999 . 10373550 . 84326 . 10.1128/mcb.19.7.5001 .
• Inada A, Someya Y, Yamada Y, Ihara Y, Kubota A, Ban N, Watanabe R, Tsuda K, Seino Y . The cyclic AMP response element modulator family regulates the insulin gene transcription by interacting with transcription factor IID . The Journal of Biological Chemistry . 274 . 30 . 21095–21103 . July 1999 . 10409662 . 10.1074/jbc.274.30.21095 . free .
• Zauli G, Secchiero P, Rodella L, Gibellini D, Mirandola P, Mazzoni M, Milani D, Dowd DR, Capitani S, Vitale M . HIV-1 Tat-mediated inhibition of the tyrosine hydroxylase gene expression in dopaminergic neuronal cells . The Journal of Biological Chemistry . 275 . 6 . 4159–4165 . February 2000 . 10660577 . 10.1074/jbc.275.6.4159 . free .

Notes and References

1. Meyer TE, Habener JF . Cyclic AMP response element binding protein CREB and modulator protein CREM are products of distinct genes . Nucleic Acids Research . 20 . 22 . 6106 . November 1992 . 1461747 . 334485 . 10.1093/nar/20.22.6106 .
2. Masquilier D, Foulkes NS, Mattei MG, Sassone-Corsi P . Human CREM gene: evolutionary conservation, chromosomal localization, and inducibility of the transcript . Cell Growth & Differentiation . 4 . 11 . 931–937 . November 1993 . 7916662 .
3. Web site: Entrez Gene: CREM cAMP responsive element modulator.
4. Foulkes NS, Sassone-Corsi P . More is better: activators and repressors from the same gene . Cell . 68 . 3 . 411–414 . February 1992 . 1739963 . 10.1016/0092-8674(92)90178-f . 34290449 .
5. Sassone-Corsi P . Transcription factors responsive to cAMP . Annual Review of Cell and Developmental Biology . 11 . 355–377 . 1995-01-01 . 8689562 . 10.1146/annurev.cb.11.110195.002035 .
6. Isoda T, Paolocci N, Haghighi K, Wang C, Wang Y, Georgakopoulos D, Servillo G, Della Fazia MA, Kranias EG, Depaoli-Roach AA, Sassone-Corsi P, Kass DA . Novel regulation of cardiac force-frequency relation by CREM (cAMP response element modulator) . FASEB Journal . 17 . 2 . 144–151 . February 2003 . 12554693 . 10.1096/fj.01-0981com . 17890025 . free .
7. Sassone-Corsi P . CREM: a master-switch regulating the balance between differentiation and apoptosis in male germ cells . Molecular Reproduction and Development . 56 . 2 Suppl . 228–229 . June 2000 . 10824972 . 10.1002/(SICI)1098-2795(200006)56:2+<228::AID-MRD2>3.0.CO;2-B . 21160055 . free .
8. Sassone-Corsi P . CREM: a master-switch governing male germ cells differentiation and apoptosis . Seminars in Cell & Developmental Biology . 9 . 4 . 475–482 . August 1998 . 9813195 . 10.1006/scdb.1998.0200 .
9. Web site: CREM (cAMP responsive element modulator). atlasgeneticsoncology.org. 2016-10-16.
10. Fimia GM, De Cesare D, Sassone-Corsi P . A family of LIM-only transcriptional coactivators: tissue-specific expression and selective activation of CREB and CREM . Molecular and Cellular Biology . 20 . 22 . 8613–8622 . November 2000 . 11046156 . 102166 . 10.1128/MCB.20.22.8613-8622.2000 .
11. Fimia GM, De Cesare D, Sassone-Corsi P . CBP-independent activation of CREM and CREB by the LIM-only protein ACT . Nature . 398 . 6723 . 165–169 . March 1999 . 10086359 . 10.1038/18237 . 4424908 . 1999Natur.398..165F .
12. Domschke K, Kuhlenbäumer G, Schirmacher A, Lorenzi C, Armengol L, DiBella D, Gratacos M, Garritsen HS, Nöthen MM, Franke P, Sand P, Fritze J, Perez G, Maier W, Sibrowski W, Estivill X, Bellodi L, Ringelstein EB, Arolt V, Martin-Santos R, Catalano M, Stögbauer F, Deckert J . Human nuclear transcription factor gene CREM: genomic organization, mutation screening, and association analysis in panic disorder . American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics . 117B . 1 . 70–78 . February 2003 . 12555239 . 10.1002/ajmg.b.10018 . 8884044 .
13. Hamilton SP, Slager SL, Mayo D, Heiman GA, Klein DF, Hodge SE, Fyer AJ, Weissman MM, Knowles JA . Investigation of polymorphisms in the CREM gene in panic disorder . American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics . 126B . 1 . 111–115 . April 2004 . 15048659 . 10.1002/ajmg.b.20121 . 43810849 .
14. Krausz C, Sassone-Corsi P . Genetic control of spermiogenesis: insights from the CREM gene and implications for human infertility . Reproductive Biomedicine Online . 10 . 1 . 64–71 . January 2005 . 15705296 . 10.1016/S1472-6483(10)60805-X . free .
15. Nantel F, Monaco L, Foulkes NS, Masquilier D, LeMeur M, Henriksén K, Dierich A, Parvinen M, Sassone-Corsi P . Spermiogenesis deficiency and germ-cell apoptosis in CREM-mutant mice . Nature . 380 . 6570 . 159–162 . March 1996 . 8600390 . 10.1038/380159a0 . 4278745 . 1996Natur.380..159N .
16. Jasem E, Nasim J, Gholamreza M, Naser S, Nader M, Maryam SL, Abbas N, Vahid R . October 2010 . 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. 10.1016/j.mefs.2010.08.002.
17. Mazaheri M, Shahdadi V, Nazari Boron A . Molecullar and biochemical effect of alcohlic extract of Alpinia galanga on rat spermatogenesis process . Iranian Journal of Reproductive Medicine . 12 . 11 . 765–770 . November 2014 . 25709632 . 4330656 .
18. Juang YT, Wang Y, Solomou EE, Li Y, Mawrin C, Tenbrock K, Kyttaris VC, Tsokos GC . Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV . The Journal of Clinical Investigation . 115 . 4 . 996–1005 . April 2005 . 15841182 . 1070410 . 10.1172/JCI22854 .