cAMP-responsive element modulator is a protein that in humans is encoded by the CREMgene,[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]
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]
↑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. ISSN1530-6860. PMID12554693.
↑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. ISSN1084-9521. PMID9813195.
↑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. PMID10086359.
↑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. ISSN1552-4841. PMID12555239.
↑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. ISSN1552-4841. PMID15048659.
Don J, Stelzer G (Feb 2002). "The expanding family of CREB/CREM transcription factors that are involved with spermatogenesis". Molecular and Cellular Endocrinology. 187 (1–2): 115–24. doi:10.1016/S0303-7207(01)00696-7. PMID11988318.
Yan C, Miller CL, Abe J (Mar 2007). "Regulation of phosphodiesterase 3 and inducible cAMP early repressor in the heart". Circulation Research. 100 (4): 489–501. doi:10.1161/01.RES.0000258451.44949.d7. PMID17332439.
Pongubala JM, Atchison ML (Apr 1995). "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): 10304–13. doi:10.1074/jbc.270.17.10304. PMID7730336.
Fujimoto T, Fujisawa J, Yoshida M (Feb 1994). "Novel isoforms of human cyclic AMP-responsive element modulator (hCREM) mRNA". Journal of Biochemistry. 115 (2): 298–303. PMID8206879.
Bodor J, Walker W, Flemington E, Spetz AL, Habener JF (Dec 1995). "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): 413–8. doi:10.1016/0014-5793(95)01299-0. PMID8549766.
Nantel F, Monaco L, Foulkes NS, Masquilier D, LeMeur M, Henriksén K, Dierich A, Parvinen M, Sassone-Corsi P (Mar 1996). "Spermiogenesis deficiency and germ-cell apoptosis in CREM-mutant mice". Nature. 380 (6570): 159–62. doi:10.1038/380159a0. PMID8600390.
Blendy JA, Kaestner KH, Weinbauer GF, Nieschlag E, Schütz G (Mar 1996). "Severe impairment of spermatogenesis in mice lacking the CREM gene". Nature. 380 (6570): 162–5. doi:10.1038/380162a0. PMID8600391.
Gellersen B, Kempf R, Telgmann R (Jan 1997). "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. doi:10.1210/me.11.1.97. PMID8994192.
Laurance ME, Kwok RP, Huang MS, Richards JP, Lundblad JR, Goodman RH (Jan 1997). "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): 2646–51. doi:10.1074/jbc.272.5.2646. PMID9006899.
Bonny C, Cooker LA, Goldberg E (Mar 1998). "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): 754–9. doi:10.1095/biolreprod58.3.754. PMID9510963.
Müller FU, Bokník P, Knapp J, Neumann J, Vahlensieck U, Oetjen E, Scheld HH, Schmitz W (Sep 1998). "Identification and expression of a novel isoform of cAMP response element modulator in the human heart". FASEB Journal. 12 (12): 1191–9. PMID9737722.
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. PMID10086359.
Inada A, Someya Y, Yamada Y, Ihara Y, Kubota A, Ban N, Watanabe R, Tsuda K, Seino Y (Jul 1999). "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): 21095–103. doi:10.1074/jbc.274.30.21095. PMID10409662.
Zauli G, Secchiero P, Rodella L, Gibellini D, Mirandola P, Mazzoni M, Milani D, Dowd DR, Capitani S, Vitale M (Feb 2000). "HIV-1 Tat-mediated inhibition of the tyrosine hydroxylase gene expression in dopaminergic neuronal cells". The Journal of Biological Chemistry. 275 (6): 4159–65. doi:10.1074/jbc.275.6.4159. PMID10660577.
