Gene Symbol: Crem
Description: cAMP responsive element modulator
Alias: Icer, cAMP-responsive element modulator, CRE modulator, cAMP responsive element moderator, inducible cyclic AMP early repressor
Species: rat
Products:     Crem

Top Publications

  1. 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
    ..Islet Genechips analysis revealed that the mRNA levels of cAMP response element modulator (CREM)-17X and inducible cAMP early repressor were significantly increased in both 27 mM glucose- and FFA-treated islets...
  2. Ding B, Abe J, Wei H, Xu H, Che W, Aizawa T, et al. A positive feedback loop of phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis. Proc Natl Acad Sci U S A. 2005;102:14771-6 pubmed
    ..was significantly reduced in human failing hearts, accompanied by up-regulation of inducible cAMP early repressor (ICER) expression...
  3. 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
    ..Because oxidised LDL diminish the expression of genes regulated by the inducible cAMP early repressor (ICER), we investigated the involvement of this transcription factor and of oxidative stress in beta cell failure ..
  4. Meyer T, Habener J. Cyclic AMP response element binding protein CREB and modulator protein CREM are products of distinct genes. Nucleic Acids Res. 1992;20:6106 pubmed
  5. Bieganska K, Figiel I, Gierej D, Kaczmarek L, Klejman A. Silencing of ICERs (Inducible cAMP Early Repressors) results in partial protection of neurons from programmed cell death. Neurobiol Dis. 2012;45:701-10 pubmed publisher
    ..of CREB/CREM/ATF transcription factors family (CREB-cAMP Responsive Element Binding protein, CREM-cAMP Responsive Element Modulator, ATF-Activating Transcription Factor) that have repeatedly been shown to have a prosurvival function...
  6. Müller F, Lewin G, Baba H, Boknik P, Fabritz L, Kirchhefer U, et al. Heart-directed expression of a human cardiac isoform of cAMP-response element modulator in transgenic mice. J Biol Chem. 2005;280:6906-14 pubmed
    ..activation mediated by cAMP-response element (CRE) and transcription factors of the CRE-binding protein (CREB)/CRE modulator (CREM) family represents an important mechanism of cAMP-dependent gene regulation possibly implicated in ..
  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
    ..Several members of the CREM/ICER (cAMP responsive element modulator/inducible cAMP early repressor) protein family may act as endogenous CREB antagonists...
  8. Steigedal T, Bruland T, Misund K, Thommesen L, Laegreid A. Inducible cAMP early repressor suppresses gastrin-mediated activation of cyclin D1 and c-fos gene expression. Am J Physiol Gastrointest Liver Physiol. 2007;292:G1062-9 pubmed
    ..cell line AR42J and that this gastrin response is inhibited by endogenous inducible cAMP early repressor (ICER)...
  9. 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
    ..There is striking circadian fluctuation of a novel CREM isoform, ICER, which is expressed at high levels during the night...

More Information


  1. Woo C, Le N, Shishido T, Chang E, Lee H, Heo K, et al. Novel role of C terminus of Hsc70-interacting protein (CHIP) ubiquitin ligase on inhibiting cardiac apoptosis and dysfunction via regulating ERK5-mediated degradation of inducible cAMP early repressor. FASEB J. 2010;24:4917-28 pubmed publisher
    ..of insulin growth factor-1 (IGF-1) was mediated by ERK5-CHIP signal module via inducible cAMP early repressor (ICER) destabilization. In vitro runoff assay and Ub assay showed ICER as a substrate of CHIP Ub ligase...
  2. Walker W, Sanborn B, Habener J. An isoform of transcription factor CREM expressed during spermatogenesis lacks the phosphorylation domain and represses cAMP-induced transcription. Proc Natl Acad Sci U S A. 1994;91:12423-7 pubmed
    cAMP response element-binding protein (CREB) and modulator protein (CREM) regulate the transcription of cAMP-responsive genes via phosphorylation by cAMP-dependent protein kinase A...
  3. Husse B, Isenberg G. CREB expression in cardiac fibroblasts and CREM expression in ventricular myocytes. Biochem Biophys Res Commun. 2005;334:1260-5 pubmed
    ..pathway is regulated by members of the cAMP response element binding protein (CREB) family consisting of CREB, CREM, and ATF-1...
  4. Matsuda M, Hyoudou T, Kadowaki M, Onuki K, Masushige S, Kida S. The administration of retinoic acid down-regulates cAMP-responsive element modulator (CREM) mRNA in vitamin A-deficient testes. Biosci Biotechnol Biochem. 2005;69:261-6 pubmed
    ..retinoic acid (ATRA) or retinol to VAD rats down-regulates the testicular mRNA levels of the cAMP responsive element modulator (CREM), an essential transcription factor for spermatogenesis...
  5. 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
    ..Palmitate treatment led to overexpression of the inducible cAMP early repressor (ICER-1gamma), which bound to a functional cAMP-response element located in the promoter of the CX36 gene...
  6. Liu Y, Aguilera G. Cyclic AMP inducible early repressor mediates the termination of corticotropin releasing hormone transcription in hypothalamic neurons. Cell Mol Neurobiol. 2009;29:1275-81 pubmed publisher
    Elevations of inducible cAMP early repressor (ICER), the repressor isoform of the cAMP-responsive element modulator (CREM), are associated with protein binding to the corticotrophin releasing hormone (CRH) promoter and termination of CRH ..
  7. Fujimoto T, Fujisawa J, Yoshida M. Novel isoforms of human cyclic AMP-responsive element modulator (hCREM) mRNA. J Biochem. 1994;115:298-303 pubmed
    ..The highly homologous protein CREM (CRE-modulator) is thought to modulate CREB-stimulated transcription, and is also involved in transcriptional ..
  8. Bisler S, Schleicher A, Gass P, Stehle J, Zilles K, Staiger J. Expression of c-Fos, ICER, Krox-24 and JunB in the whisker-to-barrel pathway of rats: time course of induction upon whisker stimulation by tactile exploration of an enriched environment. J Chem Neuroanat. 2002;23:187-98 pubmed
    ..The inducible cyclic AMP early repressor (ICER), a transcription factor of the cAMP signaling pathway, showed a maximum after 6 h, decreased ..
  9. Le N, Takei Y, Shishido T, Woo C, Chang E, Heo K, et al. p90RSK targets the ERK5-CHIP ubiquitin E3 ligase activity in diabetic hearts and promotes cardiac apoptosis and dysfunction. Circ Res. 2012;110:536-50 pubmed publisher
    ..apoptosis is one of the key events in the development and progression of heart failure, and a crucial role for ICER (inducible cAMP early repressor) in this process has been previously reported...
  10. Zmrzljak U, Korencic A, Kosir R, Golicnik M, Sassone Corsi P, Rozman D. Inducible cAMP early repressor regulates the Period 1 gene of the hepatic and adrenal clocks. J Biol Chem. 2013;288:10318-27 pubmed publisher
    ..cAMP signaling through CREM (cAMP-responsive element modulator) and its variant ICER (inducible cAMP early repressor) is linked to the ..
  11. Burkart A, Mukherjee A, Mayo K. Mechanism of repression of the inhibin alpha-subunit gene by inducible 3',5'-cyclic adenosine monophosphate early repressor. Mol Endocrinol. 2006;20:584-97 pubmed
    ..Previous studies established an important role for inducible cAMP early repressor (ICER) in repression of alpha-inhibin. These current studies investigate the mechanisms of repression by ICER...
  12. Steinbicker A, Liu H, Jiramongkolchai K, Malhotra R, Choe E, Busch C, et al. Nitric oxide regulates pulmonary vascular smooth muscle cell expression of the inducible cAMP early repressor gene. Nitric Oxide. 2011;25:294-302 pubmed publisher
    ..induced by GSNO, contain a cAMP-response element (CRE), of which one encoded the inducible cAMP early repressor (ICER)...
  13. Gautier Stein A, Zitoun C, Lalli E, Mithieux G, Rajas F. Transcriptional regulation of the glucose-6-phosphatase gene by cAMP/vasoactive intestinal peptide in the intestine. Role of HNF4alpha, CREM, HNF1alpha, and C/EBPalpha. J Biol Chem. 2006;281:31268-78 pubmed
    ..These results allow us to identify intestine-specific regulators of the Glc6Pase gene and to improve the understanding of the differences in the regulation of gluconeogenesis in the intestine compared with the liver. ..
  14. Inada A, Yamada Y, Someya Y, Kubota A, Yasuda K, Ihara Y, et al. Transcriptional repressors are increased in pancreatic islets of type 2 diabetic rats. Biochem Biophys Res Commun. 1998;253:712-8 pubmed the diabetic state, we investigated the expression and function of the transcriptional repressor CREM (CRE modulator) in rat pancreatic islets...
  15. Schwartz W, Aronin N, Sassone Corsi P. Photoinducible and rhythmic ICER-CREM immunoreactivity in the rat suprachiasmatic nucleus. Neurosci Lett. 2005;385:87-91 pubmed the cAMP response element modulator (CREM) gene, including a repressor isoform (inducible cAMP early repressor [ICER])...
  16. Wu H, Chen Y, Miao S, Zhang C, Zong S, Koide S, et al. Sperm associated antigen 8 (SPAG8), a novel regulator of activator of CREM in testis during spermatogenesis. FEBS Lett. 2010;584:2807-15 pubmed publisher
    cAMP response element modulator (CREM)-mediated gene expression is an essential regulatory mechanism for germ cell differentiation...
  17. Yanagimachi R, Wakayama T, Kishikawa H, Fimia G, Monaco L, Sassone Corsi P. Production of fertile offspring from genetically infertile male mice. Proc Natl Acad Sci U S A. 2004;101:1691-5 pubmed
  18. Oh M, Chang M, Park W, Kim D, Bae H, Huh Y, et al. Yukmijihwang-tang protects against cyclophosphamide-induced reproductive toxicity. Reprod Toxicol. 2007;24:365-70 pubmed
    ..CP diminished the expression of cAMP-responsive element modulator (CREM), a transcription factor that is highly expressed in male germ cells and is crucial to post-meiotic germ cell ..
  19. Spencer C, Jahng J, Ryu V, Houpt T. Lithium-induced gene expression of inducible cyclic adenosine monophosphate early repressor in the rat adrenal gland. J Neurosci Res. 2005;82:273-82 pubmed
    ..lithium-induced activation of the HPA axis in rats by the adrenal expression of inducible cAMP early repressor (ICER), which is activated by elevated intracellular cAMP...
  20. 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
    ..Cyclic AMP response element modulator-1 (CREM-1) is one member of the family with limited acquaintance...
  21. 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
    ..Decrease of alpha1 is dependent upon the inducible cAMP early repressor (ICER) as directly demonstrated by ICER-induced down-regulation of endogenous alpha1-containing GABA(A)Rs at the cell ..
  22. Shin S, Kim T, Lee H, Kang J, Lee J, Cho K, et al. The switching role of β-adrenergic receptor signalling in cell survival or death decision of cardiomyocytes. Nat Commun. 2014;5:5777 pubmed publisher
    ..The ERK1/2 and ICER-mediated feed-forward loop is the hidden design principle underlying such cell fate switching characteristics...
  23. Lund I, Hu Y, Raol Y, Benham R, Faris R, Russek S, et al. BDNF selectively regulates GABAA receptor transcription by activation of the JAK/STAT pathway. Sci Signal. 2008;1:ra9 pubmed publisher
    ..of STAT3 cause the adenosine 3',5'-monophosphate (cAMP) response element-binding protein (CREB) family member ICER (inducible cAMP early repressor) to bind with phosphorylated CREB at the Gabra1:CRE site...
  24. 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
    ..from the CREM/ICER gene due to use of an internal promoter (P2) placed in an intron of the CREM (cAMP responsive element modulator) gene...
  25. Jaspers S, Gellersen B, Kempf R, Samalecos A, Bergmann M, Steger K. Functional characterization of male germ cell-specific CREM isoforms. J Androl. 2007;28:59-66 pubmed
    ..promoter usage, splicing, and translational initiation, expression of the cAMP-responsive element modulator (CREM) gene results in the production of functionally different CREM proteins with either activating or repressing ..
  26. Tenbrock K, Juang Y, Tolnay M, Tsokos G. The cyclic adenosine 5'-monophosphate response element modulator suppresses IL-2 production in stimulated T cells by a chromatin-dependent mechanism. J Immunol. 2003;170:2971-6 pubmed
    ..The cAMP response element modulator (CREM) is known to form complexes with CREB and bind to the -180 site of the IL-2 promoter in anergic and in systemic ..
  27. Raghavendra Rao V, Bowen K, Dhodda V, Song G, Franklin J, Gavva N, et al. Gene expression analysis of spontaneously hypertensive rat cerebral cortex following transient focal cerebral ischemia. J Neurochem. 2002;83:1072-86 pubmed transient focal ischemia-induced brain damage [suppressor of cytokine signaling (SOCS)-3, cAMP responsive element modulator (CREM), cytosolic retinol binding protein (CRBP), silencer factor-B, survival motor neuron (SMN), ..
  28. Umesh H, Ganesh B, Reddy C. Secalonic acid D alters the expression and phosphorylation of the transcription factors and their binding to cAMP response element in developing murine secondary palate. J Craniofac Genet Dev Biol. 2000;20:173-82 pubmed
    ..its signals via the transcription factors (TF) such as cAMP response element (CRE) binding protein (CREB), CRE modulator (CREM) and activator transcription factor-1 (ATF-1) to CRE-containing genes...
  29. Wei S, Yan Z, Zhou J. Role of cAMP-responsive element modulator-tau (CREMtau) in ipsilateral testicular injury after unilateral testicular torsion-detorsion. Fertil Steril. 2008;89:1737-42 pubmed
    ..Reduction in testicular CREMtau expression may be one of the mechanisms responsible for impairment of spermatogenesis in ipsilateral testes after unilateral testicular torsion-detorsion. ..
  30. Bitar M, Al Mulla F. Upregulation of CREM/ICER suppresses wound endothelial CRE-HIF-1α-VEGF-dependent signaling and impairs angiogenesis in type 2 diabetes. Dis Model Mech. 2015;8:65-80 pubmed publisher
    ..Mechanistically, we found that oxidative stress and PKA activation in diabetes enhanced CREM/ICER expression. This reduces IRS2 cellular content by inhibiting cAMP response element (CRE) transcriptional activity...
  31. Huening M, Yehia G, Molina C, Christakos S. Evidence for a regulatory role of inducible cAMP early repressor in protein kinase a-mediated enhancement of vitamin D receptor expression and modulation of hormone action. Mol Endocrinol. 2002;16:2052-64 pubmed
    ..To understand regulatory mechanisms involved, we asked whether the inducible cAMP early repressor (ICER), which serves as a dominant negative regulator of cAMP-induced transcription in other endocrine systems, may ..
  32. Modarressi M, Behnam B, Cheng M, Taylor K, Wolfe J, van der Hoorn F. Tsga10 encodes a 65-kilodalton protein that is processed to the 27-kilodalton fibrous sheath protein. Biol Reprod. 2004;70:608-15 pubmed
    ..Our results suggest the possibility that Tsga10 plays a role in the sperm tail fibrous sheath. ..
  33. Rabionet M, van der Spoel A, Chuang C, von Tümpling Radosta B, Litjens M, Bouwmeester D, et al. Male germ cells require polyenoic sphingolipids with complex glycosylation for completion of meiosis: a link to ceramide synthase-3. J Biol Chem. 2008;283:13357-69 pubmed publisher
    ..Thus, our data imply that both glycans and the particular acyl chains of germinal sphingolipids are relevant for proper completion of meiosis. ..
  34. Haefliger J, Rohner Jeanrenaud F, Caille D, Charollais A, Meda P, Allagnat F. Hyperglycemia downregulates Connexin36 in pancreatic islets via the upregulation of ICER-1/ICER-1?. J Mol Endocrinol. 2013;51:49-58 pubmed publisher
    ..inhibition of the cAMP/PKA pathway and was associated with an overexpression of the inducible cAMP early repressor ICER-1/ICER-1?, which binds to a functional cAMP-response element in the promoter of the Cx36 gene Gjd2...
  35. Kell C, Dehghani F, Wicht H, Molina C, Korf H, Stehle J. Distribution of transcription factor inducible cyclicAMP early repressor (ICER) in rodent brain and pituitary. J Comp Neurol. 2004;478:379-94 pubmed activator cyclicAMP responsive element binding protein (CREB) and inhibitor inducible cyclicAMP early repressor (ICER), play an important role...
  36. Zhang J, Zhu Y, Liang C, Qie M, Niu R, Sun Z, et al. Effects of Fluoride on Expression of P450, CREM and ACT Proteins in Rat Testes. Biol Trace Elem Res. 2017;175:156-160 pubmed publisher
    ..Proteins cytochrome P450 (P450), cAMP-responsive element modulator (CREM), and activator of CREM in testis (ACT) play the key roles in spermatogenesis and sperm motility...