Routes of Transcriptional Activation in the Testis: CREM and its Co-Activator ACT

  • D. De Cesare
  • G. M. Fimia
  • A. Morlon
  • P. Sassone-Corsi
Conference paper
Part of the Ernst Schering Research Foundation Workshop book series (SCHERING FOUND, volume 6)


Coordinated gene expression programs govern the complex processes of cell growth and differentiation. The modulation of gene expression by specific signal transduction pathways enables cells to trigger the appropriate short- and long-term adaptation programs in response to environmental cues. Many transcription factors are final targets of specific transduction pathways. Factors of the CREB (cAMP-responsive element binding protein) family were originally identified as activators that respond directly to the cyclic AMP-dependent signaling pathway via phosphorylation by the protein kinase A (PKA) (Montminy 1997; Sassone-Corsi 1995). This family comprises a large number of proteins encoded by the CREB, CREM (cAMP-responsive element modulator) and ATF-1 (activating transcription factor 1) genes. Recently, it has become apparent that members of the CREB family play important roles in the nuclear responses to a variety of external signals. CREB and CREM have also been shown to function in many physiological systems, including memory and long-term potentiation (Silva et al. 1998), circadian rhythms (Foulkes et al. 1997), pituitary function (Struthers et al. 1991) and spermatogenesis (Sassone-Corsi 1998).


Male Germ Cell Inducible cAMP Early Repressor FHL4 Expression CREM Expression CREM Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Arany Z, Newsome D, Oldread E, Livingston DM, Eckner R (1995) A family of transcriptional adaptor proteins targeted by the El A oncoprotein. Nature 374: 81–84PubMedCrossRefGoogle Scholar
  2. Arias J, Alberts AS, Brindle P, Claret FX, Smeal T, Karin M, Feramisco J, Montminy M (1994) Activation of cAMP and mitogen responsive genes relies on a common nuclear factor. Nature 370: 226–229PubMedCrossRefGoogle Scholar
  3. Brindle P, Linke S, Montminy MR (1993) Protein-kinase A-dependent activator in transcription factor CREB reveals new role for CREM repressors. Nature 364: 821–824PubMedCrossRefGoogle Scholar
  4. Chan KK, Tsui SK, Lee SM, Luk SC, Liew CC, Fung KP, Waye MM, Lee CY (1998) Molecular cloning and characterization of FHL2, a novel LIM domain protein preferentially expressed in human heart. Gene 210: 345–350PubMedCrossRefGoogle Scholar
  5. Chrivia JC, Kwok RP, Lamb N, Hagiwara M, Montminy MR, Goodman RH (1993) Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature 365: 855–859PubMedCrossRefGoogle Scholar
  6. Cohen P (1997) The search for physiological substrates of MAP and SAP kinases in mammalian cells. Trends Cell Biol 7: 353–361PubMedCrossRefGoogle Scholar
  7. Courey AJ, Tjian R (1988) Analysis of Spl in vivo reveals multiple transcriptional domains, including a novel glutamine-rich activation motif. Cell 55: 887–898PubMedCrossRefGoogle Scholar
  8. Dawid IB, Breen JJ, Toyama R (1998) LIM domains: multiple roles as adapters and functional modifiers in protein interactions. Trends Genet 14: 156–162PubMedCrossRefGoogle Scholar
  9. De Cesare D, Fimia GM, Sassone-Corsi P (1999) Signaling routes to CREM and CREB: plasticity in transcriptional activation. Trends Biochem Sci 24: 281–285PubMedCrossRefGoogle Scholar
  10. De Cesare D, Jacquot S, Hanauer A, Sassone-Corsi P (1998) Rsk-2 activity is necessary for epidermal growth factor-induced phosphorylation of CREB protein and transcription of c-fos gene. Proc Natl Acad Sci USA 95: 12202–12207PubMedCrossRefGoogle Scholar
  11. Groot R, Ballou LM, Sassone-Corsi P (1994) Positive regulation of the cAMP-responsive activator CREM by the p70 S6 kinase: an alternative route to mitogen-induced gene expression. Cell 79: 81–91PubMedCrossRefGoogle Scholar
  12. Groot RP, den HJ, Vandenheede JR, Goris J, Sassone-Corsi P (1993) Multiple and cooperative phosphorylation events regulate the CREM activator function. EMBO J 12: 3903–3911PubMedGoogle Scholar
  13. Deak M, Clifton AD, Lucocq LM, Alessi DR (1998) Mitogen-and stress-activated protein kinase-1 (MSKI) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J 17: 4426–41PubMedCrossRefGoogle Scholar
  14. Delmas V, van dHF, Mellstrom B, Jegou B, Sassone-Corsi P (1993) Induction of CREM activator proteins in spermatids: down-stream targets and implications for haploid germ cell differentiation. Mol Endocrinol 7: 1502–1514PubMedCrossRefGoogle Scholar
  15. Eckner R, Ewen ME, Newsome D, Gerdes M, De CJ, Lawrence JB, Livingston DM (1994) Molecular cloning and functional analysis of the adenovirus ElA-associated 300-kD protein (p300) reveals a protein with properties of a transcriptional adaptor. Genes Dey 8: 869–884CrossRefGoogle Scholar
  16. Ferreri K, Gill G, Montminy M (1994) The cAMP-regulated transcription factor CREB interacts with a component of the TFIID complex. Proc Natl Acad Sci USA 91: 1210–1213PubMedCrossRefGoogle Scholar
  17. Fimia GM, De Cesare D, Sassone-Corsi P (1998) Mechanisms of activation by CREB and CREM: phosphorylation, CBP, and a novel coactivator, ACT. Cold Spring Harb Symp Quant Biol 63: 631–642Google Scholar
  18. Fimia GM, De Cesare D, Sassone-Corsi P (1999) CBP-independent activation of CREM and CREB by the LIM-only protein ACT. Nature 398: 165–169PubMedCrossRefGoogle Scholar
  19. Foulkes NS, Borjigin J, Snyder SH, Sassone-Corsi P (1997) Rhythmic transcription: the molecular basis of circadian melatonin synthesis. Trends Neurosci 20: 487–492PubMedCrossRefGoogle Scholar
  20. Foulkes NS, Borrelli E, Sassone-Corsi P (1991) CREM gene: use of alternative DNA-binding domains generates multiple antagonists of cAMP-induced transcription. Cell 64: 739–749PubMedCrossRefGoogle Scholar
  21. Foulkes NS, Mellstrom B, Benusiglio E, Sassone-Corsi P (1992) Developmental switch of CREM function during spermatogenesis: from antagonist to activator. Nature 355: 80–84PubMedCrossRefGoogle Scholar
  22. Foulkes NS, Schiotter F, Pevet P, Sassone-Corsi P (1993) Pituitary hormone FSH directs the CREM functional switch during spermatogenesis. Nature 362: 264–267PubMedCrossRefGoogle Scholar
  23. Genini M, Schwalbe P, Scholl FA, Remppis A, Mattei MG, Schafer BW (1997) Subtractive cloning and characterization of DRAL, a novel LIM-domain protein down-regulated in rhabdomyosarcoma. DNA Cell Biol 16: 433–442PubMedCrossRefGoogle Scholar
  24. Ginty DD, Bonni A, Greenberg ME (1994) Nerve growth factor activates a Ras-dependent protein kinase that stimulates c-fos transcription via phosphorylation of CREB. Cell 77: 713–725PubMedCrossRefGoogle Scholar
  25. Gonzalez GA, Montminy MR (1989) Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 59: 675–680PubMedCrossRefGoogle Scholar
  26. Hai TW, Liu F, Coukos WJ, Green MR (1989) Transcription factor ATF cDNA clones: an extensive family of leucine zipper proteins able to selectively form DNA-binding heterodimers [published erratum appears in Genes Dev 1990 Apr; 4(4):682]. Genes Dev 3: 2083–2090PubMedCrossRefGoogle Scholar
  27. Iordanov M, Bender K, Ade T, Schmid W, Sachsenmaier C, Engel K, Gaestel M, Rahmsdorf HJ, Herrlich P (1997) CREB is activated by UVC through a p38/HOG-1-dependent protein kinase. EMBO J 16: 1009–1022PubMedCrossRefGoogle Scholar
  28. Jégou B (1993) The Sertoli-germ cell communication network in mammals. Int Rev Cytol 147: 25–96PubMedCrossRefGoogle Scholar
  29. Kistler MK, Sassone-Corsi P, Kistler WS (1994) Identification of a functional cyclic adenosine 3’,5’-monophosphate response element in the 5’-flanking region of the gene for transition protein 1 (TP1), a basic chromosomal protein of mammalian spermatids. Biol Reprod 51: 1322–1329PubMedCrossRefGoogle Scholar
  30. Kouzarides T (1999) Histone acetylases and deacetylases in cell proliferation. Curr Opin Genet Dev 9: 40–48PubMedCrossRefGoogle Scholar
  31. Kwok RP, Lundblad JR, Chrivia JC, Richards JP, Bachinger HP, Brennan RG, Roberts SG, Green MR, Goodman RH (1994) Nuclear protein CBP is a coactivator for the transcription factor CREB. Nature 370: 223–226PubMedCrossRefGoogle Scholar
  32. Lalli E, Sassone-Corsi P (1994) Signal transduction and gene regulation: the nuclear response to cAMP. J Biol Chem 269: 17359–17362PubMedGoogle Scholar
  33. Lamas M, Sassone-Corsi P (1997) The dynamics of the transcriptional response to cyclic adenosine 3’,5’ -monophosphate: recurrent inducibility and refractory phase. Mol Endocrinol 11: 1415–1424PubMedCrossRefGoogle Scholar
  34. Laoide BM, Foulkes NS, Schlotter F, Sassone-Corsi P (1993) The functional versatility of CREM is determined by its modular structure. EMBO J 12: 1179–1191PubMedGoogle Scholar
  35. McKnight GS, Clegg CH, Uhler MD, Chrivia JC, Cadd GG, Correll LA, Otten AD (1988) Analysis of the cAMP-dependent protein kinase system using molecular genetic approaches. Recent Prog Horm Res 44: 307–335PubMedGoogle Scholar
  36. Molina CA, Foulkes NS, Lalli E, Sassone-Corsi P (1993) Inducibility and negative autoregulation of CREM: an alternative promoter directs the expression of ICER, an early response repressor. Cell 75: 875–886PubMedCrossRefGoogle Scholar
  37. Montminy M (1997) Transcriptional regulation by cyclic AMP. Annu Rev Biochem 66: 807–822PubMedCrossRefGoogle Scholar
  38. Morgan MJ, Madgwick AJA (1996) Slim defines a novel family of LIM-proteins expressed in skeletal muscle. Biochem Biophys Res Commun 225: 632–638PubMedCrossRefGoogle Scholar
  39. Morgan MJ, Madgwick AJA (1999) The fourth member of the FHL family of LIM proteins is expressed exclusively in the testis. Biochem Biophys Res Commun 255: 251–255PubMedCrossRefGoogle Scholar
  40. Nakajima T, Uchida C, Anderson SF, Lee CG, Hurwitz J, Parvin JD, Montminy M (1997) RNA helicase A mediates association of CBP with RNA polymerase II. Cell 90: 1107–1112PubMedCrossRefGoogle Scholar
  41. Nantel F, Monaco L, Foulkes NS, Masquilier D, Le MM, Henriksen K, Dierich A, Parvinen M, Sassone-Corsi P (1996) Spermiogenesis deficiency and germ-cell apoptosis in CREM-mutant mice. Nature 380: 159–162PubMedCrossRefGoogle Scholar
  42. Radhakrishnan I, Perez-Alvarado GC, Parker D, Dyson HJ, Montminy MR, Wright PE (1997) Solution structure of the KIX domain of CBP bound to the transactivation domain of CREB: a model for activator:coactivator interactions. Cell 91: 741–752PubMedCrossRefGoogle Scholar
  43. Rehfuss RP, Walton KM, Loriaux MM, Goodman RH (1991) The cAMP-regulated enhancer-binding protein ATF-1 activates transcription in response to cAMP-dependent protein kinase A. J Biol Chem 266: 18431–18434PubMedGoogle Scholar
  44. Roesler WJ, Vandenbark GR, Hanson RW (1988) Cyclic AMP and the induction of eukaryotic gene transcription. J Biol Chem 263: 9063–9066PubMedGoogle Scholar
  45. Rozman D, Fink M, Fimia GM, Sassone-Corsi P, Waterman MR (1999) cAMP/CREM-dependent regulation of cholesterogenic lanosterol 14-alpha demethylase (CYP51) in spermatids. Mol Endocrinol 13: 1951–1962.Google Scholar
  46. Sassone-Corsi P (1995) Transcription factors responsive to cAMP. Annu Rev Cell Dev Biol 11: 355–377PubMedCrossRefGoogle Scholar
  47. Sassone-Corsi P (1997) Transcriptional checkpoints determining the fate of male germ cells. Cell 88: 163–166PubMedCrossRefGoogle Scholar
  48. Sassone-Corsi P (1998) CREM: a master-switch governing male germ cell differentiation and apoptotis. Sem Cell Dev Biol 9: 475–482CrossRefGoogle Scholar
  49. Sassone-Corsi P, Visvader J, Ferland L, Mellon PL, Verma IM (1988) Induction of proto-oncogene fos transcription through the adenylate cyclase pathway: characterization of a cAMP-responsive element. Genes Dev 2: 1529–1538PubMedCrossRefGoogle Scholar
  50. Schmeichel KL, Beckerle MC (1994) The LIM domain is a modular protein-binding interface. Cell 79: 211–219PubMedCrossRefGoogle Scholar
  51. Sheng M, Thompson MA, Greenberg ME (1991) CREB: a Ca2+-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science 252: 1427–1430PubMedCrossRefGoogle Scholar
  52. Shikama N, Lyon J, La Thangue NB (1997) The p300/CBP family: integrating signals with transcription factors and chromatin. Trends Cell Biol 7: 230–236CrossRefGoogle Scholar
  53. Silva AJ, Kogan JH, Frankland PW, Kida S (1998) CREB and memory. Annu Rev Neurosci 21: 127–148PubMedCrossRefGoogle Scholar
  54. Struthers RS, Vale WW, Arias C, Sawchenko PE, Montminy MR (1991) Somatotroph hypoplasia and dwarfism in transgenic mice expressing a non-phosphorylatable CREB mutant. Nature 350: 622–624PubMedCrossRefGoogle Scholar
  55. Sun Z, Sassone-Corsi P, Means AR (1995) Calspermin gene transcription is regulated by two cyclic AMP response elements contained in an alternative promoter in the calmodulin kinase IV gene. Mol Cell Biol 15: 561–571PubMedGoogle Scholar
  56. Tan Y, Rouse J, Zhang A, Cariati S, Cohen P, Comb MJ (1996) FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. EMBO J 15: 4629–4642PubMedGoogle Scholar
  57. Taniguchi Y, Furukawa T, Tun T, Han H, Honjo T (1998) LIM protein KyoT2 negatively regulates transcription by association with the RBP-J DNA-binding protein. Mol Cell Biol 18: 644–654PubMedGoogle Scholar
  58. Williams T, Admon A, Luscher B, Tjian R (1988) Cloning and expression of AP-2, a cell-type-specific transcription factor that activates inducible enhancer elements. Genes Dev 2: 1557–1569PubMedCrossRefGoogle Scholar
  59. Xing J, Ginty DD, Greenberg ME (1996) Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science 273: 959–963PubMedCrossRefGoogle Scholar
  60. Zhou Y, Sun Z, Means AR, Sassone CP, Bernstein KE (1996) cAMP-response element modulator tau is a positive regulator of testis angiotensin converting enzyme transcription. Proc Natl Acad Sci USA 93: 12262–12266Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2000

Authors and Affiliations

  • D. De Cesare
  • G. M. Fimia
  • A. Morlon
  • P. Sassone-Corsi

There are no affiliations available

Personalised recommendations