CREM: A Transcriptional Master Switch Governing the cAMP Response in the Testis

  • L. Monaco
  • F. Nantel
  • N. S. Foulkes
  • P. Sassone-Corsi
Part of the Ernst Schering Research Foundation Workshop book series (SCHERING FOUND, volume 2/1996)


The structural organization of most transcription factors is intrinsically modular, in most cases including a DNA-binding domain and an activation domain. It has been shown that these domains can be interchanged between different factors and still retain their functional properties. This modularity suggests that during evolution, the increasing complexity of gene expression may have resulted not only by duplication and divergence of existing genes, but also by a domain shuffling process to generate factors with novel properties (Harrison 1991). An important step forward in the study of transcription factors has been the discovery that many constitute final targets of specific signal transduction pathways. The two major signal transduction systems are those including cAMP and diacylglycerol (DAG) as second messengers (Nishizuka 1986). Each pathway is also characterized by a specific protein kinase (protein kinase A (PKA) and protein kinase C (PKC), respectively) and its ultimate target DNA control element [cAMP-responsive element (CRE) and TPA-responsive element (TRE), respectively]. Although initially characterized as distinct systems, accumulating evidence points towards extensive cross-talk between these pathways (Cambier et al. 1987; Yoshimasa et al. 1987; Masquilier and Sassone-Corsi 1992).


Sertoli Cell Seminiferous Epithelium Inducible cAMP Early Repressor Adenylyl Cyclase Pathway CREM Expression 
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  1. Arany Z, Newsome D, Oldread E, Livingston DM, Eckner R (1995) A family of transcriptional adaptor proteins targeted by the E1A oncoprotein. Nature 374:81–84.PubMedCrossRefGoogle Scholar
  2. Baba T, Niida Y, Michikawa Y, Kashiwabara SI, Kodaira K, Takenada M, Kohno N, Gerton G, Arai Y (1994) An acrosomal protein, sp32, in mammalian sperm is a binding protein specific for two proacrosins and an acrosin intermediate. J Biol Chem 269:10133–10140.PubMedGoogle Scholar
  3. Borrelli E, Montmayeur JP, Foulkes NS, Sassone-Corsi P (1992) Signal transduction and gene control: the cAMP pathway. Crit Rev Oncog 3:321–338.PubMedGoogle Scholar
  4. Cambier JC, Newell MK, Justement LB, McGuire JC, Leach KL, Chen ZZ (1987) Ia binding ligands and cAMP stimulate nuclear translocation of PKC in B lymphocytes. Nature 327:629–632.PubMedCrossRefGoogle Scholar
  5. Chaganti RS, German J (1979) Human male fertility, probably genetically determined, due to defective meiosis and spermatogenic arrest. Am J Hum Genet 31:634–641.PubMedGoogle Scholar
  6. Chevrier P, Zerial M, Lemaire P, Almendral J, Bravo R, Charnay P (1988) A gene encoding a protein with zinc fingers is activated during Go/Gi transition in cultured cells. EMBO J 7:29–35.Google Scholar
  7. Chrivia, JC, Kwok RPS, Lamb N, Haniwawa M, Montminy MR, Goodman RH (1993) Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature 365:855–859.PubMedCrossRefGoogle Scholar
  8. Courey AJ, Tjian R (1989) Analysis of Sp1 in vivo reveals multiple transcriptional domains, including a novel glutamine activation motif. Cell 55:887–898.CrossRefGoogle Scholar
  9. Dash PK, Karl KA, Colicos MA, Prywes R, Kandel ER (1991) cAMP response element-binding protein is activated by Ca2+/calmodulin as well as cAMP-dependent protein kinase. Proc Natl Acad Sci USA 88:5061–5065.PubMedCrossRefGoogle Scholar
  10. de Groot RP, den Hertog J, Vandenheede JR, Goris J, Sassone-Corsi P (1993a) Multiple and cooperative phosphorylation events regulate the CREM activator function. EMBO J 12:3903–3911.PubMedGoogle Scholar
  11. de Groot RP, Derua R, Goris J, Sassone-Corsi P (1993b) Phosphorylation and negative regulation of the transcriptional activator CREM by p34cdc2. Mol Endocrinol 7:1495–1501.PubMedCrossRefGoogle Scholar
  12. de Groot RP, 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 79:81–91.PubMedCrossRefGoogle Scholar
  13. Delmas V, Sassone-Corsi P (1994) The central role of CREM in the cAMP signalling pathway in testis. Mol Cell Endocrinol 100:121–124.PubMedCrossRefGoogle Scholar
  14. Delmas V, van der Hoorn F, Mellström B, Jégou B, Sassone-Corsi P (1993) Induction of CREM activator proteins in spermatids: down-stream targets and implications for haploid germ cell differentiation. Mol Endocrinol 7:1502–1514.PubMedCrossRefGoogle Scholar
  15. Desdouets C, Matesic G, Molina CA, Foulkes NS, Sassone-Corsi P, Brechot C, Sobczak-Thepot J (1995) Cell cycle regulation of cyclin A gene expression by the cyclic AMP-responsive transcription factors CREB and CREM. Mol Cell Biol 15:3301–3309.PubMedGoogle Scholar
  16. Foulkes NS, Sassone-Corsi P (1992) More is better: activators and repressors from the same gene. Cell 68:411–414.PubMedCrossRefGoogle Scholar
  17. Foulkes NS, Borrelli E, Sassone-Corsi P (1991) CREM gene: Use of alternative DNA binding domains generates multiple antagonists of cAMP-induced transcription. Cell 64:739–749.PubMedCrossRefGoogle Scholar
  18. Foulkes NS, Mellstrom B, Benusiglio E, Sassone-Corsi P (1992) Developmental switch of CREM function during spermatogenesis: from antagonist to transcriptional activator. Nature 355:80–84.PubMedCrossRefGoogle Scholar
  19. Foulkes NS, Schlotter F, Pévet P, Sassone-Corsi P (1993) Pituitary hormone FSH directs the CREM functional switch during spermatogenesis. Nature 362:264–267.PubMedCrossRefGoogle Scholar
  20. Fritz IB (1978) Site of action of androgens and follicle-stimulating hormone on cells of the seminiferous tubule. In: Litwach G (ed) Biochemical actions of hormones. Academic, New York, pp 249–281.CrossRefGoogle Scholar
  21. Ginty DD, Glowacka D, Bader DS, Hidaka H, Wagner JA (1991) Induction of immediate early genes by Ca2+ influx requires cAMP-dependent protein kinase in PC12 cells. J Biol Chem 266:17454–17458.PubMedGoogle Scholar
  22. Gonzalez GA, Montminy MR (1989) Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at Ser 133. Cell 59:675–680.PubMedCrossRefGoogle Scholar
  23. Greenberg ME, Hermanowski AL, Ziff EB (1986) Effect of protein synthesis inhibitors on growth factor activation of c-fos, c-myc, and actin gene transcription. Mol Cell Biol 6:1050–1057.PubMedGoogle Scholar
  24. Hagiwara M, Alberts A, Brindle P, Meinkoth J, Feramisco J, Deng T, Karin M, Shenolikar S, Montminy M (1992) Transcriptional attenuation following cAMP induction requires PP-1-mediated dephosphorylation of CREB. Cell 70:105–113.PubMedCrossRefGoogle Scholar
  25. Hai T-Y, Curran T (1991) Cross-family dimerization of transcription factors Fos: Jun and ATF/CREB alters DNA binding specificity. Proc Natl Acad Sci USA 88:3720–3724.PubMedCrossRefGoogle Scholar
  26. Hai T-Y, 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. Genes Dev 3:2083–2090.PubMedCrossRefGoogle Scholar
  27. Hall SH, Joseph DR, Conti M (1988) Follicle-stimulating hormone induces transient expression of the protooncogene c-fos in primary Sertoli cell cultures. Mol Endocrinol 2:55–61.PubMedCrossRefGoogle Scholar
  28. Hamil KG, Hall SH (1994) Cloning of rat Sertoli cell follicle-stimulating hormone primary response complementary deoxyribonucleic acid: regulation of TSC-22 gene expression. Endocrinology 134:1205–1212.PubMedCrossRefGoogle Scholar
  29. Hamil KG, Conti M, Shimasaki S, Hall SH (1994) Follicle-stimulating hormone regulation of AP1: inhibition of c-jun and stimulation of jun-B gene transcription in the rat Sertoli cell. Mol Cell Endocrinol 99:269–277.PubMedCrossRefGoogle Scholar
  30. Harrison SC (1991) A structural taxonomy of DNA-binding domains. Nature 353:715–719.PubMedCrossRefGoogle Scholar
  31. Heckert LL, Daley IJ, Griswold MD (1992) Structural organization of the follicle-stimulating hormone receptor gene. Mol Endocrinol 6:70–80.PubMedCrossRefGoogle Scholar
  32. Henriksen K, Hakovirta H, Parvinen M (1995a) In situ quantification of stage-specific apoptosis in the rat seminiferous epithelium: effects of short-term experimental cryptorchidism. Int J Androl (in press).Google Scholar
  33. Henriksen K, Hakovirta H, Parvinen M (1995b) Testosterone inhibits and induces apoptosis in rat seminiferous tubules in a stage-specific manner: in situ quantification in squash preparations after administration of ethane di-methane sulfonate. Endocrinology 136:3285–3291.PubMedCrossRefGoogle Scholar
  34. Hoeffler JP, Meyer TE, Yun Y, Jameson JL, Habener JF (1988) Cyclic AMP responsive DNA-binding protein: structure based on a cloned placental cDNA. Science 242:1430–1433.PubMedCrossRefGoogle Scholar
  35. Hummler E, Cole TJ, Blendy JA, Ganss R, Aguzzi A, Schmid W, Beermann F, Schütz G (1994) Targeted mutation of the CREB gene: compensation within the CREB/ATF family of transcription factors. Proc Natl Acad Sci USA 91:5647–5651.PubMedCrossRefGoogle Scholar
  36. Jégou B, Syed V, Sourdaine P, Byers S, Gérard N, Velez de la Calle J, Pineau C, Garnier DH, Bauché F (1992) The dialogue between late spermatids and Sertoli cells in vertebrates: a century of research. In: Nieschlag E, Habenicht U-F (eds) Spermatogenesis. Fertilization. Contraception. Molecular, cellular and endocrine events in male reproduction. Springer, Berlin Heidelberg New York, pp 56–95 (Ernst Schering Research Foundation Workshop, vol 4).Google Scholar
  37. Kistler M, Sassone-Corsi P, Kistler SW (1994) Identification of a functional cAMP response element in the 5′-flanking region of the gene for transition protein 1 (TP1), a basic chromosomal protein of mammalian spermatids. Biol Reprod 51:1322–1329.PubMedCrossRefGoogle Scholar
  38. Kwok RP, Lundblad J, 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 370:223–226.PubMedCrossRefGoogle Scholar
  39. Lalli E, Sassone-Corsi P (1994) Signal transduction and gene regulation: the nuclear response to cAMP. J Biol Chem 269:17359–17362.PubMedGoogle Scholar
  40. Lalli E, Sassone-Corsi P (1995) Long-term desensitization of the TSH receptor involves TSH-directed induction of CREM in the thyroid gland. Proc Natl Acad Sci USA 92:9633–9637.PubMedCrossRefGoogle Scholar
  41. Laoide BM, Foulkes NF, Schlotter F, Sassone-Corsi P (1993) The functional versatility of CREM is determined by its modular structure. EMBO J 12:1179–1191.PubMedGoogle Scholar
  42. Lee CQ, Yun Y, Hoeffler JP, Habener JF (1990) Cyclic-AMP-responsive transcriptional activation involves interdependent phosphorylated subdomains. EMBO J 9:4455–4465.PubMedGoogle Scholar
  43. Lemaire P, Relevant O, Bravo R, Charnay P (1988) Two mouse genes encoding potential transcription factors with identical DNA-binding domains are activated by growth factors in cultured cells. Proc Natl Acad Sci USA 85:4691–4695.PubMedCrossRefGoogle Scholar
  44. Masquilier D, Sassone-Corsi P (1992) Transcriptional cross-talk: nuclear factors CREM and CREB bind to AP-1 sites and inhibit activation by Jun. J Biol Chem 267:22460–22466.PubMedGoogle Scholar
  45. McKnight SG, 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. Rec Prog Horm Res 44:307–335.PubMedGoogle Scholar
  46. Means AR, Dedman JR, Tash JS, Tindall DJ, van Sickle M, Welsh MJ (1980) Regulation of the testis Sertoli cell by follicle-stimulating hormone. Annu Rev Physiol 42:59–70.PubMedCrossRefGoogle Scholar
  47. Mellström B, Naranjo JR, Foulkes NS, Lafarga M, Sassone-Corsi P (1993) Transcriptional response to cAMP in brain: specific distribution and induction of CREM antagonists. Neuron 10:655–665.PubMedCrossRefGoogle Scholar
  48. Micic M, Nikolis J, Micic S (1992) Clinical and meiotic studies in an infertile man with Y; 13 translocation. Hum Reprod 7:1118–1120.PubMedGoogle Scholar
  49. 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 75:875–886.PubMedCrossRefGoogle Scholar
  50. Monaco L, Foulkes NS, Sassone-Corsi P (1995) Pituitary follicle-stimulating hormone (FSH) induces CREM gene expression in Sertoli cells: involvement in long-term desensitization of the FSH receptor. Proc Natl Acad Sci USA 92:10673–10677.PubMedCrossRefGoogle Scholar
  51. Nichols M, Weih F, Schmid W, DeVack C, Kowenz-Leutz E, Luckow B, Bo-shart M, Schütz G (1992) Phosphorylation of CREB affects its binding to high and low affinity sites: implications for cAMP induced gene transcription. EMBO J 11:3337–3346.PubMedGoogle Scholar
  52. Nishizuka Y (1986) Studies and perspectives of protein kinase C. Science 233:305–312.PubMedCrossRefGoogle Scholar
  53. Parvinen M (1982) Regulation of the seminiferous epithelium. Endocr Rev 3:404–417.PubMedCrossRefGoogle Scholar
  54. Parvinen M, Hecht NB (1981) Identification of living spermatogenic cells of the mouse by transillumination-phase contrast microscopic technique for “in situ” analyses of DNA polymerase activities. Histochemistry 71:567–579.PubMedCrossRefGoogle Scholar
  55. Perey B, Clermont Y, Leblond CP (1961) The wave of the seminiferous epithelium. Am J Anat 108:47–77.CrossRefGoogle Scholar
  56. Propst F, Rosenberg MP, Vande Woude GF (1988) Proto-oncogene expression in germ cell development. Trends Genet 4:183–187.PubMedCrossRefGoogle Scholar
  57. Rehfuss RP, Walton KM, Loriaux MM, Goodman RH (1991) The cAMP-rgulated enhancer-binding protein ATF-1 activations transcription in response to cAMP-dependent protein kinase A. J Biol Chem 266:18431–18434.PubMedGoogle Scholar
  58. Roesler WJ, Vanderbark GR, Hanson RW (1988) Cyclic AMP and the induction of eukaryotic gene expression. J Biol Chem 263:9063–9066.PubMedGoogle Scholar
  59. Rubin MR, Nguyen-Huu MC (1991) Murine embryonic spinal cord and adult testis Hox-1.4 cDNAs are identical 3′ to the homeobox. DNA Seq 1:329–334.PubMedGoogle Scholar
  60. Ruppert S, Cole TJ, Boshart M, Schmid E, Schütz G (1992) Multiple mRNA isoforms of the transcription activator protein CREB: generation by alternative splicing and specific expression in primary spermatocytes. EMBO J 11:1503–1512.PubMedGoogle Scholar
  61. Santen RJ (1987) The testis. In: Felig P, Baxter JD, Broadus AE, Frohman LA (eds) Endocrinology and metabolism. McGraw-Hill, New York, pp 821–905.Google Scholar
  62. Sassone-Corsi P (1988) Cyclic AMP induction of early adenovirus promoters involves sequences required for E1A-transactivation. Proc Natl Acad Sci USA 85:7192–7196.PubMedCrossRefGoogle Scholar
  63. Sassone-Corsi P (1994a) Rhythmic transcription and autoregulatory loops: winding up the biological clock. Cell 78:361–364.PubMedCrossRefGoogle Scholar
  64. Sassone-Corsi P (1994b) The nuclear response to cAMP during spermatogenesis: the key role of transcription factor CREM. In: Verhoeven G, Habenicht UF (eds) Molecular and cellular endocrinology of the testis. Springer, Berlin Heidelberg New York, pp 219–252 (Ernst Schering Research Foundation Workshop, Suppl 1).Google Scholar
  65. 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 2:1529–1538.PubMedCrossRefGoogle Scholar
  66. Sassone-Corsi P, Ransone LJ, Verma IM (1990) Cross-talk in signal transduction: TPA-inducible factor Jun/AP-1 activates cAMP responsive enhancer elements. Oncogene 5:427–431.PubMedGoogle Scholar
  67. Sheng M, McFadden G, Greenberg ME (1990) Membrane depolarization and calcium induce c-fos transcription via phosphorylation of transcription factor CREB. Neuron 4:571–582.PubMedCrossRefGoogle Scholar
  68. Skinner MK (1991) Cell-cell interactions in the testis. Endocr Rev 12:45–77.PubMedCrossRefGoogle Scholar
  69. Stehle JH, Foulkes NS, Molina CA, Simonneaux V, Pévet P, Sassone-Corsi P (1993) Adrenergic signals direct rhythmic expression of transcriptional repressor CREM in the pineal gland. Nature 365:314–320.PubMedCrossRefGoogle Scholar
  70. Sun Z, Sassone-Corsi P, Means A (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 15:561–571.PubMedGoogle Scholar
  71. Themmen APN, Blok LJ, Post M, Baarends WM, Hoogerbrugge JW, Parmen-tier M, Vassart G, Grootegoed JA (1991) Follitropin receptor down-regulation involves a cAMP-dependent post-transcriptional decrease of receptor mRNA expression. Mol Cell Endocrinol 78:R7–R13.PubMedCrossRefGoogle Scholar
  72. Verma IM, Sassone-Corsi P (1987) Proto-oncogene fos: complex but versatile regulation. Cell 51:513–514.PubMedCrossRefGoogle Scholar
  73. Waeber G, Meyer TE, LeSieur M, Hermann HL, Gérard N, Habener JF (1991) Developmental stage-specific expression of cyclic adenosine 3′,5′-monophosphate response element-binding protein CREB during spermatogenesis involves alternative exon splicing. Mol Endocrinol 5:1418–1430.PubMedCrossRefGoogle Scholar
  74. 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 2:1557–1569.PubMedCrossRefGoogle Scholar
  75. Wolgemuth DJ, Watrin F (1991) List of cloned mouse genes with unique expression pattern during spermatogenesis. Mammalian Genome 1:283–288.PubMedCrossRefGoogle Scholar
  76. Yoshimasa T, Sibley DR, Bouvier M, Lefkowitz RJ, Caron MG (1987) Crosstalk between cellular signalling pathways suggested by phorbol ester adenylate cyclase phosphorylation. Nature 327:67–70.PubMedCrossRefGoogle Scholar
  77. Ziff EB (1990) Transcription factors: a new family gathers at the cAMP response site. Trends Genet 6:69–72.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1996

Authors and Affiliations

  • L. Monaco
  • F. Nantel
  • N. S. Foulkes
  • P. Sassone-Corsi

There are no affiliations available

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