cyclic amp response element modulator


Summary: Cyclic AMP response element modulator is a basic leucine zipper transcription factor that is regulated by CYCLIC AMP. It plays an important role in SPERMATID development in the mammalian TESTIS.

Top Publications

  1. Mouravlev A, Young D, During M. Phosphorylation-dependent degradation of transgenic CREB protein initiated by heterodimerization. Brain Res. 2007;1130:31-7 pubmed
    ..Hence, heterodimerization of unphosphorylated CREB with either A-CREB or ICER triggers CREB protein degradation, whereas phosphorylation prevents CREB from such degradation both in vitro and in vivo. ..
  2. Monaco L, Kotaja N, Fienga G, Hogeveen K, Kolthur U, Kimmins S, et al. Specialized rules of gene transcription in male germ cells: the CREM paradigm. Int J Androl. 2004;27:322-7 pubmed
    ..The function of ACT was found to be regulated by the testis-specific kinesin KIF17b. Here we discuss some aspects of the testis-specific transcription machinery, whose function is essential for the process of spermatogenesis. ..
  3. Chelu M, Sarma S, Sood S, Wang S, van Oort R, Skapura D, et al. Calmodulin kinase II-mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice. J Clin Invest. 2009;119:1940-51 pubmed
    ..Together, these findings suggest that increased RyR2-dependent Ca2+ leakage due to enhanced CaMKII activity is an important downstream effect of CaMKII in individuals susceptible to AF induction. ..
  4. Zhou Y, Marlen K, Palma J, Schweitzer A, Reilly L, Gregoire F, et al. Overexpression of repressive cAMP response element modulators in high glucose and fatty acid-treated rat islets. A common mechanism for glucose toxicity and lipotoxicity?. J Biol Chem. 2003;278:51316-23 pubmed
    ..Taken together, these data suggest that up-regulation of CREM repressors by either FFA or high glucose exacerbates beta-cell failure in type 2 diabetes by suppressing insulin gene transcription. ..
  5. Peri A, Conforti B, Baglioni Peri S, Luciani P, Cioppi F, Buci L, et al. Expression of cyclic adenosine 3',5'-monophosphate (cAMP)-responsive element binding protein and inducible-cAMP early repressor genes in growth hormone-secreting pituitary adenomas with or without mutations of the Gsalpha gene. J Clin Endocrinol Metab. 2001;86:2111-7 pubmed
  6. Iannello R, Gould J, Young J, Giudice A, Medcalf R, Kola I. Methylation-dependent silencing of the testis-specific Pdha-2 basal promoter occurs through selective targeting of an activating transcription factor/cAMP-responsive element-binding site. J Biol Chem. 2000;275:19603-8 pubmed
    ..Our data support the notion that hypomethylation and transcription factor recruitment are necessary events that precede gene activation at the early stages of spermatogenesis. ..
  7. Macho B, Brancorsini S, Fimia G, Setou M, Hirokawa N, Sassone Corsi P. CREM-dependent transcription in male germ cells controlled by a kinesin. Science. 2002;298:2388-90 pubmed
    ..Thus, a kinesin directly controls the activity of a transcriptional coactivator by a tight regulation of its intracellular localization. ..
  8. Hu Y, Lund I, Gravielle M, Farb D, Brooks Kayal A, Russek S. Surface expression of GABAA receptors is transcriptionally controlled by the interplay of cAMP-response element-binding protein and its binding partner inducible cAMP early repressor. J Biol Chem. 2008;283:9328-40 pubmed publisher
  9. Allagnat F, Alonso F, Martin D, Abderrahmani A, Waeber G, Haefliger J. ICER-1gamma overexpression drives palmitate-mediated connexin36 down-regulation in insulin-secreting cells. J Biol Chem. 2008;283:5226-34 pubmed
    ..This Cx36 down-regulation may contribute to the reduced glucose sensitivity and altered insulin secretion observed during the pre-diabetic stage and in the metabolic syndrome. ..

More Information


  1. Ho A, Terriff D, Price D, Wloka M, Chik C. The role of inducible repressor proteins in the adrenergic induction of arylalkylamine-N-acetyltransferase and mitogen-activated protein kinase phosphatase-1 in rat pinealocytes. Endocrinology. 2007;148:743-51 pubmed
  2. Christensen G, Wooding S, Ivanov I, Atkins J, Carrell D. Sequencing and haplotype analysis of the activator of CREM in the testis (ACT) gene in populations of fertile and infertile males. Mol Hum Reprod. 2006;12:257-62 pubmed
    ..We identified one ACT haplotype that had a 45% reduction in its interaction with CREM. Our results suggest that different haplotypes within the ACT gene may contribute to male factor subfertility. ..
  3. Kotaja N, Macho B, Sassone Corsi P. Microtubule-independent and protein kinase A-mediated function of kinesin KIF17b controls the intracellular transport of activator of CREM in testis (ACT). J Biol Chem. 2005;280:31739-45 pubmed
    ..These results indicate that cyclic AMP signaling controls CREM-mediated transcription in male germ cells through modification of KIF17b function. ..
  4. Fimia G, Morlon A, Macho B, De Cesare D, Sassone Corsi P. Transcriptional cascades during spermatogenesis: pivotal role of CREM and ACT. Mol Cell Endocrinol. 2001;179:17-23 pubmed
    ..ACT is coordinately expressed with CREM, associates with it and confers a powerful transcriptional activation function. It is able to bypass the classical requirement of CREM phosphorylation and recruiting of CBP. ..
  5. Nantel F, Monaco L, Foulkes N, Masquilier D, LeMeur M, Henriksen K, et al. Spermiogenesis deficiency and germ-cell apoptosis in CREM-mutant mice. Nature. 1996;380:159-62 pubmed
    ..We show that CREM deficiency results in the lack of postmeiotic cell-specific gene expression. The complete lack of spermatozoa in the mutant mice is reminiscent of cases of human infertility. ..
  6. Maronde E, Pfeffer M, Olcese J, Molina C, Schlotter F, Dehghani F, et al. Transcription factors in neuroendocrine regulation: rhythmic changes in pCREB and ICER levels frame melatonin synthesis. J Neurosci. 1999;19:3326-36 pubmed
    ..Consequently, a silenced ICER expression in pinealocytes leads to a disinhibited arylalkylamine-N-acetyltransferase transcription and a primarily enhanced melatonin synthesis. ..
  7. Jaworski J, Mioduszewska B, Sánchez Capelo A, Figiel I, Habas A, Gozdz A, et al. Inducible cAMP early repressor, an endogenous antagonist of cAMP responsive element-binding protein, evokes neuronal apoptosis in vitro. J Neurosci. 2003;23:4519-26 pubmed
    ..We suggest that the naturally occurring CREB functional antagonist ICER may have a specific function in programmed cell death of neurons, probably by silencing the expression of anti-apoptotic genes. ..
  8. Favre D, Niederhauser G, Fahmi D, Plaisance V, Brajkovic S, Beeler N, et al. Role for inducible cAMP early repressor in promoting pancreatic beta cell dysfunction evoked by oxidative stress in human and rat islets. Diabetologia. 2011;54:2337-46 pubmed publisher
    ..Induction of ICER links oxidative stress to beta cell failure caused by oxidised LDL and can be effectively abrogated by antioxidant treatment. ..
  9. Krausz C, Sassone Corsi P. Genetic control of spermiogenesis: insights from the CREM gene and implications for human infertility. Reprod Biomed Online. 2005;10:64-71 pubmed
    ..The conservation of these elements and of their regulatory functions in human spermatogenesis indicates that they are likely to provide important insights into understanding the molecular mechanisms of human infertility. ..
  10. Molina C, Foulkes N, Lalli E, Sassone Corsi P. Inducibility and negative autoregulation of CREM: an alternative promoter directs the expression of ICER, an early response repressor. Cell. 1993;75:875-86 pubmed
    ..A cluster of four CREs in this promoter directs cAMP inducibility. ICER binds to these elements and thereby represses the activity of its own promoter, thus constituting a negative autoregulatory loop. ..
  11. Stehle J, von Gall C, Korf H. Analysis of cell signalling in the rodent pineal gland deciphers regulators of dynamic transcription in neural/endocrine cells. Eur J Neurosci. 2001;14:1-9 pubmed
  12. Porter B, Lund I, Varodayan F, Wallace R, Blendy J. The role of transcription factors cyclic-AMP responsive element modulator (CREM) and inducible cyclic-AMP early repressor (ICER) in epileptogenesis. Neuroscience. 2008;152:829-36 pubmed publisher
    ..Together these data suggest that the increase in ICER mRNA following SE may have a role in suppressing the severity of epilepsy. ..
  13. Gellersen B, Kempf R, Sandhowe R, Weinbauer G, Behr R. Novel leader exons of the cyclic adenosine 3',5'-monophosphate response element modulator (CREM) gene, transcribed from promoters P3 and P4, are highly testis-specific in primates. Mol Hum Reprod. 2002;8:965-76 pubmed
    ..Furthermore, we show differential activation of P1, P3 and P4 during mouse postnatal testicular development, suggesting cell- and stage-specific regulatory mechanisms for these CREM promoters. ..
  14. Steger K, Behr R, Kleiner I, Weinbauer G, Bergmann M. Expression of activator of CREM in the testis (ACT) during normal and impaired spermatogenesis: correlation with CREM expression. Mol Hum Reprod. 2004;10:129-35 pubmed
    ..Our findings indicate a conserved function of ACT during the evolution of mammalian spermatogenesis and suggest a role for CREM in ACT transcriptional regulation. ..
  15. Mioduszewska B, Jaworski J, Kaczmarek L. Inducible cAMP early repressor (ICER) in the nervous system--a transcriptional regulator of neuronal plasticity and programmed cell death. J Neurochem. 2003;87:1313-20 pubmed
    ..ICER expression is inducible in the brain and in neuronal culture by a variety of stimuli. As a CREB antagonist, ICER appears to be of pivotal importance in neuronal plasticity and programmed cell death. ..
  16. Acimovic J, Fink M, Pompon D, Bjorkhem I, Hirayama J, Sassone Corsi P, et al. CREM modulates the circadian expression of CYP51, HMGCR and cholesterogenesis in the liver. Biochem Biophys Res Commun. 2008;376:206-10 pubmed publisher
    ..We propose that cAMP signaling might generally be involved in the circadian regulation of cholesterol synthesis on the periphery. ..
  17. Rajkovic M, Middendorff R, Wetzel M, Frkovic D, Damerow S, Seitz H, et al. Germ cell nuclear factor relieves cAMP-response element modulator tau-mediated activation of the testis-specific promoter of human mitochondrial glycerol-3-phosphate dehydrogenase. J Biol Chem. 2004;279:52493-9 pubmed
  18. Tomita H, Nazmy M, Kajimoto K, Yehia G, Molina C, 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. 2003;93:12-22 pubmed
  19. Mayr B, Montminy M. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol. 2001;2:599-609 pubmed
    ..CREB is phosphorylated in response to various signals, but how is specificity achieved in these signalling pathways? ..
  20. Staiger J, Bisler S, Schleicher A, Gass P, Stehle J, Zilles K. Exploration of a novel environment leads to the expression of inducible transcription factors in barrel-related columns. Neuroscience. 2000;99:7-16 pubmed
    ..e. the trigeminal nuclei and the ventrobasal complex. These results strongly suggest that a coordinated transcriptional response is initiated in the barrel cortex as a consequence of processing of novel environmental stimuli. ..
  21. Storvik M, Linden A, Kontkanen O, Lakso M, Castren E, Wong G. Induction of cAMP response element modulator (CREM) and inducible cAMP early repressor (ICER) expression in rat brain by uncompetitive N-methyl-D-aspartate receptor antagonists. J Pharmacol Exp Ther. 2000;294:52-60 pubmed
    ..These results provide evidence for the involvement of CREM and ICER family transcription factors in the pharmacologic effects of uncompetitive NMDA receptor antagonists. ..
  22. Sassone Corsi P. CREM: a master-switch regulating the balance between differentiation and apoptosis in male germ cells. Mol Reprod Dev. 2000;56:228-9 pubmed
    ..Recent results have shown that CREM needs a tissue-specific co-activator, ACT (activator of CREM in testis) to elicit its regulatory function in testis. ..
  23. Hummler E, Cole T, Blendy J, Ganss R, Aguzzi A, Schmid W, et al. Targeted mutation of the CREB gene: compensation within the CREB/ATF family of transcription factors. Proc Natl Acad Sci U S A. 1994;91:5647-51 pubmed
  24. Klejman A, Kaczmarek L. Inducible cAMP early repressor (ICER) isoforms and neuronal apoptosis in cortical in vitro culture. Acta Neurobiol Exp (Wars). 2006;66:267-72 pubmed
    ..The most efficiently induced, as well as the most effective in evoking neuronal cell death, were both ICER Igamma and IIgamma isoforms. ..
  25. Misund K, Steigedal T, Laegreid A, Thommesen L. Inducible cAMP early repressor splice variants ICER I and IIgamma both repress transcription of c-fos and chromogranin A. J Cell Biochem. 2007;101:1532-44 pubmed
    ..The proliferation rate was not altered in cells overexpressing ICER I or IIgamma. Thus, in the epithelial cells HEK 293, ICER I and IIgamma splice variants seem to exert similar biological function. ..
  26. Mioduszewska B, Jaworski J, Szklarczyk A, Klejman A, Kaczmarek L. Inducible cAMP early repressor (ICER)-evoked delayed neuronal death in the organotypic hippocampal culture. J Neurosci Res. 2008;86:61-70 pubmed
    ..These results underscore the usefulness of the organotypic cultures for studies of neurodegeneration and point to neuronal loss having a multifaceted nature in a complex cellular environment. ..
  27. Rozman D, Fink M, Fimia G, Sassone Corsi P, Waterman M. Cyclic adenosine 3',5'-monophosphate(cAMP)/cAMP-responsive element modulator (CREM)-dependent regulation of cholesterogenic lanosterol 14alpha-demethylase (CYP51) in spermatids. Mol Endocrinol. 1999;13:1951-62 pubmed
    ..While in somatic cells all genes involved in cholesterol biosynthesis are regulated coordinately by the sterol/SREBP-signaling pathway, male germ cells contain alternate routes to control expression of cholesterogenic genes. ..
  28. Inada A, Someya Y, Yamada Y, Ihara Y, Kubota A, Ban N, et al. The cyclic AMP response element modulator family regulates the insulin gene transcription by interacting with transcription factor IID. J Biol Chem. 1999;274:21095-103 pubmed
    We analyzed a mechanism of transcriptional regulation of the human insulin gene by cyclic AMP response element modulator (CREM) through four cyclic AMP response elements (CREs)...
  29. Beissbarth T, Borisevich I, Hörlein A, Kenzelmann M, Hergenhahn M, Klewe Nebenius A, et al. Analysis of CREM-dependent gene expression during mouse spermatogenesis. Mol Cell Endocrinol. 2003;212:29-39 pubmed
  30. Mantamadiotis T, Lemberger T, Bleckmann S, Kern H, Kretz O, Martin Villalba A, et al. Disruption of CREB function in brain leads to neurodegeneration. Nat Genet. 2002;31:47-54 pubmed
    ..The striatal phenotype is reminiscent of Huntington disease and is consistent with the postulated role of CREB-mediated signaling in polyglutamine-triggered diseases. ..
  31. Foulkes N, Borrelli E, Sassone Corsi P. CREM gene: use of alternative DNA-binding domains generates multiple antagonists of cAMP-induced transcription. Cell. 1991;64:739-49 pubmed
    ..CREM proteins reveal the same efficiency and specificity of binding to CRE sequences as CREB, but in contrast to CREB, CREM acts as a down-regulator of cAMP-induced transcription. ..
  32. Hisano M, Yamada S, Tanaka H, Nishimune Y, Nozaki M. Genomic structure and promoter activity of the testis haploid germ cell-specific intronless genes, Tact1 and Tact2. Mol Reprod Dev. 2003;65:148-56 pubmed
    ..Transient promoter analyses indicate that CREMtau may activate Tact1 and Tact2 expression in germ cells. ..
  33. Pigazzi M, Manara E, Beghin A, Baron E, Tregnago C, Basso G. ICER evokes Dusp1-p38 pathway enhancing chemotherapy sensitivity in myeloid leukemia. Clin Cancer Res. 2011;17:742-52 pubmed publisher
    ..ICER restoration or DUSP1 inhibition might be possible strategies to sensitize AML cancer cells to conventional chemotherapy and to inhibit tumor growth. ..
  34. Kimmins S, Kotaja N, Fienga G, Kolthur U, Brancorsini S, Hogeveen K, et al. A specific programme of gene transcription in male germ cells. Reprod Biomed Online. 2004;8:496-500 pubmed
    ..The function of ACT is regulated by a testis-specific kinesin, KIF17b. This study discusses some aspects of the testis-specific transcription machinery, the function of which is essential for the process of spermatogenesis. ..
  35. Inada A, Hamamoto Y, Tsuura Y, Miyazaki J, Toyokuni S, Ihara Y, et al. Overexpression of inducible cyclic AMP early repressor inhibits transactivation of genes and cell proliferation in pancreatic beta cells. Mol Cell Biol. 2004;24:2831-41 pubmed
    ..These results suggest that CRE and CRE-binding factors have an important role in pancreatic beta-cell physiology not only directly by regulation of gene trans-activation but also indirectly by regulation of beta-cell mass. ..
  36. Blendy J, Kaestner K, Schmid W, Gass P, Schutz G. Targeting of the CREB gene leads to up-regulation of a novel CREB mRNA isoform. EMBO J. 1996;15:1098-106 pubmed
  37. De Cesare D, Fimia G, Sassone Corsi P. Signaling routes to CREM and CREB: plasticity in transcriptional activation. Trends Biochem Sci. 1999;24:281-5 pubmed
    ..Thus, in some circumstances, CREM can bypass the classical requirement for phosphorylation and association with CBP. ..
  38. Green T, Alibhai I, Hommel J, DiLeone R, Kumar A, Theobald D, et al. Induction of inducible cAMP early repressor expression in nucleus accumbens by stress or amphetamine increases behavioral responses to emotional stimuli. J Neurosci. 2006;26:8235-42 pubmed
    ..These results suggest that ICER is an important mechanism for modulating CRE-mediated transcription in the nucleus accumbens. ..
  39. Stehle J, Foulkes N, Molina C, Simonneaux V, Pevet P, Sassone Corsi P. Adrenergic signals direct rhythmic expression of transcriptional repressor CREM in the pineal gland. Nature. 1993;365:314-20 pubmed
    ..Rhythmic adrenergic signals originated by the clock direct ICER expression by stimulation of the cAMP signal transduction pathway. ..
  40. Charron M, Shaper N, Rajput B, Shaper J. A novel 14-base-pair regulatory element is essential for in vivo expression of murine beta4-galactosyltransferase-I in late pachytene spermatocytes and round spermatids. Mol Cell Biol. 1999;19:5823-32 pubmed
    ..Furthermore, when the TASS-1 motif was mutated by transversion, within the context of the original 796-bp fragment, transgene expression was reduced 12- to 35-fold in vivo. ..
  41. Daniel P, Rohrbach L, Habener J. Novel cyclic adenosine 3',5'-monophosphate (cAMP) response element modulator theta isoforms expressed by two newly identified cAMP-responsive promoters active in the testis. Endocrinology. 2000;141:3923-30 pubmed
  42. Fimia G, De Cesare D, Sassone Corsi P. A family of LIM-only transcriptional coactivators: tissue-specific expression and selective activation of CREB and CREM. Mol Cell Biol. 2000;20:8613-22 pubmed
    ..The future identification of additional partners of FHL proteins is likely to reveal unappreciated aspects of tissue-specific transcriptional regulation. ..
  43. Steger K, Klonisch T, Gavenis K, Behr R, Schaller V, Drabent B, et al. 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. J Androl. 1999;20:747-54 pubmed
    ..CREM is involved in the regulation of TNP1 gene expression and consequently plays a vital role in the correct differentiation step from round spermatids to mature spermatozoa. ..
  44. Foulkes N, Mellstrom B, Benusiglio E, Sassone Corsi P. Developmental switch of CREM function during spermatogenesis: from antagonist to activator. Nature. 1992;355:80-4 pubmed
    ..This splicing-dependent reversal in CREM function represents an important example of developmental modulation in gene expression. ..
  45. Wu X, Jin W, Liu X, Fu H, Gong P, Xu J, et al. Cyclic AMP response element modulator-1 (CREM-1) involves in neuronal apoptosis after traumatic brain injury. J Mol Neurosci. 2012;47:357-67 pubmed publisher
    ..b>Cyclic AMP response element modulator-1 (CREM-1) is one member of the family with limited acquaintance...
  46. Hogeveen K, Sassone Corsi P. Regulation of gene expression in post-meiotic male germ cells: CREM-signalling pathways and male fertility. Hum Fertil (Camb). 2006;9:73-9 pubmed
    ..This sophisticated and complex regulation of gene expression in post-meiotic germ cells is governed by unique mechanisms specific to these cells and is fundamental to male fertility. ..
  47. Kimmins S, Kotaja N, Davidson I, Sassone Corsi P. Testis-specific transcription mechanisms promoting male germ-cell differentiation. Reproduction. 2004;128:5-12 pubmed
    ..In this review we summarize recent advances in the transcription machinery that is testis-specific, gene-selective and necessary for the process of spermatogenesis. ..
  48. Conti A, Kuo Y, Valentino R, Blendy J. Inducible cAMP early repressor regulates corticosterone suppression after tricyclic antidepressant treatment. J Neurosci. 2004;24:1967-75 pubmed
  49. De Cesare D, Fimia G, Brancorsini S, Parvinen M, Sassone Corsi P. Transcriptional control in male germ cells: general factor TFIIA participates in CREM-dependent gene activation. Mol Endocrinol. 2003;17:2554-65 pubmed
    ..The two proteins also colocalize intracellularly in spermatocyte and spermatid cells. These findings contribute to the understanding of the highly specialized rules of transcriptional regulation in haploid germ cells. ..
  50. Nantel F, Sassone Corsi P. CREM: a transcriptional master switch during the spermatogenesis differentiation program. Front Biosci. 1996;1:d266-9 pubmed
    ..These results demonstrate the essential role of CREM in spermatogenesis and are reminiscent of some cases of male infertility. ..
  51. Kojima N, Borlikova G, Sakamoto T, Yamada K, Ikeda T, Itohara S, et al. Inducible cAMP early repressor acts as a negative regulator for kindling epileptogenesis and long-term fear memory. J Neurosci. 2008;28:6459-72 pubmed publisher
  52. Peri A, Serio M. The CREM system in human spermatogenesis. J Endocrinol Invest. 2000;23:578-83 pubmed
    ..Other reports have confirmed our data, supporting the hypothesis that CREM plays a role also in human spermatogenesis and that the absence of "the CREM switch" can be associated to spermatogenic arrest. ..
  53. Moulton V, Holcomb D, Zajdel M, Tsokos G. Estrogen upregulates cyclic AMP response element modulator ? expression and downregulates interleukin-2 production by human T lymphocytes. Mol Med. 2012;18:370-8 pubmed publisher
    ..We previously showed that the expression of the transcriptional repressor cyclic AMP response element modulator ? (CREM?) is increased in SLE T cells and contributes to reduced IL-2 production...