Behavior Genetics

, Volume 36, Issue 3, pp 439–453 | Cite as

Transcriptional Dysregulation in Down Syndrome: Predictions for Altered Protein Complex Stoichiometries and Post-translational Modifications, and Consequences for Learning/Behavior Genes ELK, CREB, and the Estrogen and Glucocorticoid Receptors


The phenotype of Down syndrome, trisomy of chromosome 21, is hypothesized to be produced by the increased expression due to gene dosage of normal chromosome 21 genes. Chromosome 21 encodes a number of proteins that, based on experimental evidence or domain composition, are classed as transcription factors or their co-regulators. Other chromosome 21 proteins contribute to post-translational modification of transcription factors, including their phosphorylation, dephosphorylation and sumoylation. Several of these chromosome 21 proteins and the pathways in which they function have overlapping transcription factor specificities. Thus, altered stoichiometry in complexes and altered levels of activation of individual transcription factors may contribute to the Down syndrome phenotype by perturbation of downstream gene expression. Here we review recent data on four chromosome 21 proteins: NRIP1, GABPA, DYRK1A and SUMO3. We discuss the implications for activation of ELK, CREB, C/EBP \(\alpha,\beta\), estrogen and glucocorticoid receptors, and for expression of BDNF. Each of these proteins is relevant to learning, behavior and/or development and therefore perturbation of their activation may contribute to the Down syndrome phenotype.


CREB Down syndrome ELK phosphorylation sumoylation transcription factor 


  1. Ahi J., Radulovic J. and Spiess J. (2004). The role of hippocampal signaling cascades in consolidation of fear memory. Behav. Brain Res. 149:17–31PubMedCrossRefGoogle Scholar
  2. Akeson E. C., Lambert J. P., Narayanswami S., Gardiner K., Bechtel L. J. and Davisson M. T. (2001). Ts65Dn – localization of the translocation breakpoint and trisomic gene content in a mouse model for Down syndrome. Cytogenet. Cell Genet. 93:270–276PubMedCrossRefGoogle Scholar
  3. Amano K., Sago H., Uchikawa C., Suzuki T., Kotliarova S. E., Nukina N., Epstein C. J. and Yamakawa K. (2004). Dosage-dependent over-expression of genes in the trisomic region of Ts1Cje mouse model for Down syndrome. Hum. Mol. Genet. 13:1333–40PubMedCrossRefGoogle Scholar
  4. Ayberk K. M., Ilker K. M., Dierssen M. and Ceri D. D. (2004). Deficits of neuronal density in CA1 and synaptic density in the dentate gyrus, CA3 and CA1, in a mouse model of Down syndrome. Brain Res. 1022:101-109CrossRefGoogle Scholar
  5. Bambrick L. L., Yarowsky P. J. and Krueger B. K. (2003). Altered astrocyte calcium homeostasis and proliferation in theTs65Dn mouse, a model of Down syndrome. J. Neurosci. Res. 73:89–94PubMedCrossRefGoogle Scholar
  6. Begay V., Smink J. and Leutz A. (2004). Essential requirement of CCAAT/enhancer binding proteins in embryogenesis. Mol Cell Biol. 24:9744–51PubMedCrossRefGoogle Scholar
  7. Bimonte-Nelson H. A., Hunter C. L., Nelson M. E. and Granholm A. C. (2003). Frontal cortex BDNF levels correlate with working memory in an animal model of Down syndrome. Behav. Brain Res. 139:47–57PubMedCrossRefGoogle Scholar
  8. Bohren K. M., Nadkarni V., Song J. H., Gabbay K. H. and Owerbach D. (2004) A M55V polymorphism in a novel SUMO gene (SUMO-4) differentially activates heat shock transcription factors and is associated with susceptibility to type I diabetes mellitus. J. Biol. Chem. 279:27233–27238PubMedCrossRefGoogle Scholar
  9. Branchi I., Bichler Z., Minghetti L., Delabar J. M., Malchiodi-Albedi F., Gonzalez M. C., Chettouh Z., Nicolini A., Chabert C., Smith D. J., Rubin E. M., Migliore-Samour D. and Alleva E. (2004). Transgenic mouse in vivo library of human Down syndrome critical region 1: association between DYRK1A overexpression, brain development abnormalities, and cell cycle protein alteration. J Neuropathol Exp Neurol. 63:429–440PubMedGoogle Scholar
  10. Brinton R. D. (2001). Cellular and molecular mechanisms of estrogen regulation of memory function and neuroprotection against Alzheimer’s disease: recent insights and remaining challenges. Learn Mem. 8:121–133PubMedCrossRefGoogle Scholar
  11. Brinton R. D. (2004). Impact of estrogen therapy on Alzheimer’s disease: a fork in the road?. CNS Drugs 18:405–422PubMedCrossRefGoogle Scholar
  12. Busciglio J., Pelsman A., Wong C., Pigino G., Yuan M., Mori H. and Yankner B. A. (2002). Altered metabolism of the amyloid beta precursor protein is associated with mitochondrial dysfunction in Down’s syndrome. Neuron 33:677–688PubMedCrossRefGoogle Scholar
  13. Castet A., Boulahtouf A., Versini G., Bonnet S., Augereau P., Vignon F., Khochbin S., Jalaguier S. and Cavailles V. (2004). Multiple domains of the Receptor-Interacting Protein 140 contribute to transcription inhibition. Nucleic Acids Res. 32:1957–1966PubMedCrossRefGoogle Scholar
  14. Cataldo A. M., Petanceska S., Peterhoff C. M., Terio N. B., Epstein C. J., Villar A., Carlson E. J., Staufenbiel M. and Nixon R. A. (2003). App gene dosage modulates endosomal abnormalities of Alzheimer’s disease in a segmental trisomy 16 mouse model of down syndrome. J Neurosci. 23:6788–6792PubMedGoogle Scholar
  15. Cavailles V., Dauvois S., L’Horset F., Lopez G., Hoare S., Kushner P. J. and Parker M. G. (1995). Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor. EMBO J 14:3741–3751PubMedGoogle Scholar
  16. Chan R. Y., Boudreau-Lariviere C., Angus L. M., Mankal F. A. and Jasmin B. J. (1999). An intronic enhancer containing an N-box motif is required for synapse- and tissue-specific expression of the acetylcholinesterase gene in skeletal muscle fibers. Proc. Natl. Acad. Sci. USA 96:4627–4632PubMedCrossRefADSGoogle Scholar
  17. Chang K. T., Shi Y. J. and Min K. T. (2003). The Drosophila homolog of Down’s syndrome critical region 1 gene regulates learning: implications for mental retardation. Proc. Natl. Acad. Sci. USA 100:15794–15799PubMedCrossRefADSGoogle Scholar
  18. Cooper J. D., Salehi A., Delcroix J. D., Howe C. L., Belichenko P. V., Chua-Couzens J., Kilbridge J. F., Carlson E. J., Epstein C. J. and Mobley W. C. (2001) Failed retrograde transport of NGF in a mouse model of Down’s syndrome: reversal of cholinergic neurodegenerative phenotypes following NGF infusion. Proc. Natl. Acad. Sci. USA 98:10439–10444PubMedCrossRefADSGoogle Scholar
  19. Crnic L. S., Pennington B. F. (2000) Down syndrome: neuropsychology and animal models. Progr. Infancy Res. 1: 69–111Google Scholar
  20. Davisson M. T., Costa A. C. S. (1999) Mouse models of Down syndrome. In: Popko B. (eds) Mouse models in the study of genetic neurological disorders. Advances in neurochemistry. Plenum Press, New York, pp. 297–327Google Scholar
  21. Dhandapani K. M., Brann D. W. (2002) Protective effects of estrogen and selective estrogen receptor modulators in the brain. Biol. Reprod. 67: 1379–1385PubMedCrossRefGoogle Scholar
  22. Dauphinot L., Lyle R., Rivals I., Dang M. T., Moldrich R. X., Golfier G., Ettwiller L., Toyama K., Rossier J., Personnaz L., Antonarakis S. E., Epstein C. J., Sinet P. M., Potier M. C. (2005) The cerebellar transcriptome during postnatal development of the Ts1Cje mouse, a segmental trisomy model for Down syndrome. Hum. Mol. Genet. 14: 373–384PubMedCrossRefGoogle Scholar
  23. Eaton E. M., Sealy L. (2003) Modification of CCAAT/enhancer-binding protein-beta by the small ubiquitin-like modifier (SUMO) family members, SUMO-2 and SUMO-3. J. Biol. Chem. 278: 33416–33421PubMedCrossRefGoogle Scholar
  24. Engidawork E., Lubec G. (2003) Molecular changes in fetal Down syndrome brain. J. Neurochem. 84: 895–904PubMedCrossRefGoogle Scholar
  25. Epstein C. J. (1981) The consequences of chromosome imbalance: principles, mechanisms, models. Cambridge University Press, New YorkGoogle Scholar
  26. Ermak G., Harris C. D., Davies K. J. (2002) The DSCR1 (Adapt78) isoform 1 protein calcipressin 1 inhibits calcineurin and protects against acute calcium-mediated stress damage, including transient oxidative stress. FASEB J. 16: 814–824PubMedCrossRefGoogle Scholar
  27. Fromm L., Burden S. J. (2001) Neuregulin-1-stimulated phosphorylation of GABP in skeletal muscle cells. Biochemistry. 40: 5306–5312PubMedCrossRefGoogle Scholar
  28. Galceran J., de Graaf K., Tejedor F. J., Becker W. (2003) The MNB/DYRK1A protein kinase: genetic and biochemical properties. J. Neural Transm. Suppl. 67: 139–148PubMedGoogle Scholar
  29. Gardiner K., Fortna A., Bechtel L., Davisson M. T. (2003) Mouse models of Down syndrome: how useful can they be? Comparison of the gene content of human chromosome 21 with orthologous mouse genomic regions. Gene 318: 137–147PubMedCrossRefGoogle Scholar
  30. Gardiner K. (2004) Gene-dosage effects in Down syndrome and trisomic mouse models. Genome Biol. 5: 244–247PubMedCrossRefGoogle Scholar
  31. Gardiner K., Davisson M. T., Crnic L. S. (2004) Building protein interaction maps for Down’s syndrome. Brief Funct. Genom. Proteom. 3: 142–156CrossRefGoogle Scholar
  32. Gill G. (2003) Post-translational modification by the small ubiquitin-related modifier SUMO has big effects on transcription factor activity. Curr. Opin. Genet. Dev. 13: 108–113PubMedCrossRefGoogle Scholar
  33. Gocke C. B., Yu H., Kang J. (2005) Systematic identification and analysis of mammalian small ubiquitin-like modifier substrates. J. Biol. Chem. 280: 5004–5012PubMedCrossRefGoogle Scholar
  34. Granholm A. C., Ford K. A., Hyde L. A., Bimonte H. A., Hunter C. L., Nelson M., Albeck D., Sanders L. A., Mufson E. J., Crnic L. S. (2002) Estrogen restores cognition and cholinergic phenotype in an animal model of Down syndrome. Physiol. Behav. 77: 371–385PubMedCrossRefGoogle Scholar
  35. Groth R. D., Mermelstein P. G. (2003) Brain-derived neurotrophic factor activation of NFAT (nuclear factor of activated T-cells)-dependent transcription: a role for the transcription factor NFATc4 in neurotrophin-mediated gene expression. J. Neurosci. 23: 8125–8134PubMedGoogle Scholar
  36. Groth R. D., Dunbar R. L., Mermelstein P. G. (2003) Calcineurin regulation of neuronal plasticity. Biochem. Biophys. Res. Commun. 311: 1159–1171PubMedCrossRefGoogle Scholar
  37. Helguera P., Pelsman A., Pigino G., Wolvetang E., Head E., Busciglio J. (2005) ets-2 promotes the activation of a mitochondrial death pathway in Down’s syndrome neurons. J. Neurosci. 25: 2295–2303PubMedCrossRefGoogle Scholar
  38. Holmstrom S., Van Antwerp M. E., Iniguez-Lluhi J. A. (2003) Direct and distinguishable inhibitory roles for SUMO isoforms in the control of transcriptional synergy. Proc. Natl. Acad. Sci. USA 100: 15758–15763PubMedCrossRefADSGoogle Scholar
  39. Holtzman D. M., Santucci D., Kilbridge J., Chua-Couzens J., Fontana D. J., Daniels S. E., Johnson R. M., Chen K., Sun Y., Carlson E., Alleva E., Epstein C. J., Mobley W. C. (1996) Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome. Proc. Natl. Acad. Sci. USA 93: 13333–8PubMedCrossRefADSGoogle Scholar
  40. Hyde L. A., Frisone D. F., Crnic L. S. (2001) Ts65Dn mice, a model for Down syndrome, have deficits in context discrimination learning suggesting impaired hippocampal function. Behav. Brain Res. 118: 53–60PubMedCrossRefGoogle Scholar
  41. Hyde L. A., Crnic L. S. (2001) Age-related deficits in context discrimination learning in Ts65Dn mice that model Down syndrome and Alzheimer’s disease. Behav. Neurosci. 115: 1239–1246PubMedCrossRefGoogle Scholar
  42. Insausti A. M., Megias M., Crespo D., Cruz-Orive L. M., Dierssen M., Vallina I. F., Insausti R., Florez J. (1998) Hippocampal volume and neuronal number in Ts65Dn mice: a murine model of Down syndrome. Neurosci. Lett. 253: 175–178PubMedCrossRefGoogle Scholar
  43. Kahlem P., Sultan M., Herwig R., Steinfath M., Balzereit D., Eppens B., Saran N. G., Pletcher M. T., South S. T., Stetten G., Lehrach H., Reeves R. H., Yaspo M. L. (2004) Transcript level alterations reflect gene dosage effects across multiple tissues in a mouse model of down syndrome. Genome Res. 14: 1258–1267PubMedCrossRefGoogle Scholar
  44. Kellendonk C., Gass P., Kretz O., Schutz G., Tronche F. (2002) Corticosteroid receptors in the brain: gene targeting studies. Brain Res. Bull. 57: 73–83PubMedCrossRefGoogle Scholar
  45. Kleschevnikov A. M., Belichenko P. V., Villar A. J., Epstein C. J., Malenka R. C., Mobley W. C. (2004) Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome. J. Neurosci. 24: 8153–8160PubMedCrossRefGoogle Scholar
  46. Korenberg J. R., Chen X.-N., Schipper R., Sun Z., Gonsky R., Gerwehr S., Carpenter N., Daumer C., Dignan P., Disteche C. et al. (1994) Down syndrome phenotypes: the consequences of chromosomal imbalance. Proc. Natl. Acad. Sci. USA 91: 4997–5001PubMedCrossRefADSGoogle Scholar
  47. Kotaja N., Karvonen U., Janne O. A., Palvimo J. J. (2002) The nuclear receptor interaction domain of GRIP1 is modulated by covalent attachment of SUMO-1. J. Biol. Chem. 277: 30283–30288PubMedCrossRefGoogle Scholar
  48. Kramer D., Fresu L., Ashby D. S., Freeman T. C., Genazzani A. A. (2003) Calcineurin controls the expression of numerous genes in cerebellar granule cells. Mol Cell Neurosci. 23: 325–330PubMedCrossRefGoogle Scholar
  49. Lapenta V., Chiurazzi P., van der Spek P., Pizzuti A., Hanaoka F., Brahe C. (1997) SMT3A, a human homologue of the S. cerevisiae SMT3 gene, maps to chromosome 21qter and defines a novel gene family Genomics 40: 362–366PubMedCrossRefGoogle Scholar
  50. Lee J. I., Ahnn J. (2004) Calcineurin in animal behavior. Mol. Cells 17: 390–396PubMedGoogle Scholar
  51. Li Y., Wang H., Wang S., Quon D., Liu Y. W., Cordell B. (2003) Positive and negative regulation of APP amyloidogenesis by sumoylation. Proc. Natl. Acad. Sci. USA 100: 259–264PubMedCrossRefADSGoogle Scholar
  52. Lonze B. E., Ginty D. D. (2002) Function and regulation of CREB family transcription factors in the nervous system20. Neuron 35: 605–623PubMedCrossRefGoogle Scholar
  53. Lott I. T., Head E. (2001) Down syndrome and Alzheimer’s disease: a link between development and aging. Ment. Retard. Dev. Disabil. Res. Rev. 7: 172–178PubMedCrossRefGoogle Scholar
  54. Lund P. K., Hoyt E. C., Bizon J., Smith D. R., Haberman R., Helm K., Gallagher M. (2004) Transcriptional mechanisms of hippocampal aging. Exp. Gerontol. 39: 1613–1622PubMedCrossRefGoogle Scholar
  55. Lyle R., Gehrig C., Neergaard-Henrichsen C., Deutsch S., Antonarakis S. E. (2004) Gene expression from the aneuploid chromosome in a trisomy mouse model of down syndrome. Genome Res. 14: 1268–1274PubMedCrossRefGoogle Scholar
  56. Mansuy I. M. (2003) Calcineurin in memory and bidirectional plasticity. Biochem. Biophys. Res. Commun. 311: 1195–1208PubMedCrossRefGoogle Scholar
  57. Mao J., Maye P., Kogerman P., Tejedor F. J., Toftgard R., Xie W., Wu G., Wu D. (2002) Regulation of Gli1 transcriptional activity in the nucleus by Dyrk1. J. Biol. Chem. 277: 35156–35161PubMedCrossRefGoogle Scholar
  58. Mao R., Zielke C. L., Zielke H. R., Pevsner J. (2003) Global up-regulation of chromosome 21 gene expression in the developing Down syndrome brain. Genomics 81: 457–467PubMedCrossRefGoogle Scholar
  59. McEwen B. (2002) Estrogen actions throughout the brain. Recent Prog. Horm. Res. 57: 357–384PubMedCrossRefGoogle Scholar
  60. Michels F., Stam J. C., Hordijk P. L., van der Kammen R. A., Ruuls-Van Stalle L., Feltkamp C. A., Collard J. G. (1997) Regulated membrane localization of Tiam1, mediated by the NH2-terminal Pleckstrin homology domain, is required for Rac-dependent membrane ruffling and c-Jun NH2-terminal kinase activation. J. Cell Biol. 137: 387–398CrossRefGoogle Scholar
  61. Mohney, R. P., Das, M., Bivona, T. G., Hanes, R., Adams, A. G., Philips, M. R., and O’Bryan, J. P. (2003). Intersectin activates Ras but stimulates transcription through an independent pathway involving JNK. J. Biol. Chem. 278: 47038–47045Google Scholar
  62. Morris A. F., Vaughan S. E., Vaccaro P. (1982) Measurements of neuromuscular tone and strength in Down’s syndrome children. J. Ment. Defic. Res. 26: 41–46PubMedGoogle Scholar
  63. Motonaga K., Itoh M., Hirayama A., Hirano S., Becker L. E., Goto Y., Takashima S. (2001) Up-regulation of E2F-1 in Down’s syndrome brain exhibiting neuropathological features of Alzheimer-type dementia. Brain Res. 905: 250–253PubMedCrossRefGoogle Scholar
  64. Muller M., Holsboer F., Keck M. E. (2002) Genetic modification of corticosteroid receptor signalling: novel insights into pathophysiology and treatment strategies of human affective disorders. Neuropeptides 36: 117–1131PubMedCrossRefGoogle Scholar
  65. O’Leary D. A., Pritchard M. A., Xu D., Kola I., Hertzog P. J., Ristevski S. (2004) Tissue-specific overexpression of the HSA21 gene GABPalpha: implications for DS. Biochim. Biophys. Acta 1739: 81–87PubMedGoogle Scholar
  66. Olson L. E., Richtsmeier J. T., Leszl J., Reeves R. H. (2004a) A chromosome 21 critical region does not cause specific Down syndrome phenotypes. Science 306: 687–690CrossRefADSGoogle Scholar
  67. Olson L. E., Roper R. J., Baxter L. L., Carlson E. J., Epstein C. J., Reeves R. H. (2004b) Down syndrome mouse models Ts65Dn, Ts1Cje, and Ms1Cje/Ts65Dn exhibit variable severity of cerebellar phenotypes. Dev. Dyn. 230: 581–589CrossRefGoogle Scholar
  68. Oitzl M. S., Reichardt H. M., Joels M., de Kloet E. R. (2001) Point mutation in the mouse glucocorticoid receptor preventing DNA binding impairs spatial memory. Proc. Natl. Acad. Sci. USA 98: 12790–12795PubMedCrossRefADSGoogle Scholar
  69. Parker A. W., Bronks R., Snyder C. W. Jr. (1986) Walking patterns in Down’s syndrome. J. Ment. Defic. Res. 30: 317–330PubMedGoogle Scholar
  70. Pennington B. F., Moon J., Edgin J., Stedron J., Nadel L. (2003) The neuropsychology of Down syndrome: evidence for hippocampal dysfunction. Child Dev. 74: 75–93PubMedCrossRefGoogle Scholar
  71. Robert I., Sutter A., Quirin-Stricker C. (2002) Synergistic activation of the human choline acetyltransferase gene by c-Myb and C/EBPbeta. Brain Res. Mol. Brain Res. 106: 124–135PubMedCrossRefGoogle Scholar
  72. Rosmarin A. G., Resendes K. K., Yang Z., McMillan J. N., Fleming S. L. (2004) GA-binding protein transcription factor: a review of GABP as an integrator of intracellular signaling and protein–protein interactions. Blood Cells Mol. Dis. 32: 143–154PubMedCrossRefGoogle Scholar
  73. Rothermel B. A., Vega R. B., Williams R. S. (2003) The role of modulatory calcineurin-interacting proteins in calcineurin signaling. Trends Cardiovasc. Med. 13: 15–21PubMedCrossRefGoogle Scholar
  74. Saitoh H., Hinchey J.(2000) Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3. J. Biol. Chem. 275: 6252–6258PubMedCrossRefGoogle Scholar
  75. Salinas S., Briancon-Marjollet A., Bossis G., Lopez M. A., Piechaczyk M., Jariel-Encontre I., Debant A., Hipskind R. A. (2004) SUMOylation regulates nucleo-cytoplasmic shuttling of Elk-1. J. Cell Biol. 165: 767–773PubMedCrossRefGoogle Scholar
  76. Sananbenesi F., Fischer A., Schrick C., Spiess J., Radulovic J. (2002) Phosphorylation of hippocampal Erk-1/2, Elk-1, and p90-Rsk-1 during contextual fear conditioning: interactions between Erk-1/2 and Elk-1. Mol. Cell Neurosci. 21: 463–476PubMedCrossRefGoogle Scholar
  77. Seeler J. S., Dejean A. (2003) Nuclear and unclear functions of SUMO. Nat. Rev. Mol. Cell Biol. 4: 690–699PubMedCrossRefGoogle Scholar
  78. Sementchenko V. I., Watson D. K. (2000) Ets target genes: past, present and future. Oncogene 19: 6533–6548PubMedCrossRefGoogle Scholar
  79. Sgambato V., Vanhoutte P., Pages C., Rogard M., Hipskind R., Besson M. J., Caboche J. (1998) In vivo expression and regulation of Elk-1, a target of the extracellular-regulated kinase signaling pathway, in the adult rat brain. J. Neurosci. 18: 214–226PubMedGoogle Scholar
  80. Shieh P. B., Hu S. C., Bobb K., Timmusk T., Ghosh A. (1998) Identification of a signaling pathway involved in calcium regulation of BDNF expression. Neuron. 20: 727–740PubMedCrossRefGoogle Scholar
  81. Sitz J. H., Tigges M., Baumgartel K., Khaspekov L. G., Lutz B. (2004) Dyrk1A potentiates steroid hormone-induced transcription via the chromatin remodeling factor Arip4. Mol. Cell Biol. 24: 5821–5834PubMedCrossRefGoogle Scholar
  82. Slemmon J. R., Morgan J. I., Fullerton S. M., Danho W., Hilbush B. S., Wengenack T. M. (1996) Camstatins are peptide antagonists of calmodulin based upona conserved structural motif in PEP-19, neurogranin and neuromodulin. J. Biol. Chem. 271: 15911–15917PubMedCrossRefGoogle Scholar
  83. Slepnev V. I., De Camilli P. (2000) Accessory factors in clathrin-dependent synaptic vesicle endocytosis. Nat. Rev. Neurosci. 1: 161–172PubMedCrossRefGoogle Scholar
  84. Smith D. J., Stevens M. E., Sudanagunta S. P., Bronson R. T., Makhinson M., Watabe A. M., O’Dell T. J., Fung J., Weier H. U., Cheng J. F., Rubin E. M. (1997) Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome. Nat. Genet. 16: 28–36PubMedCrossRefGoogle Scholar
  85. Stasko M. R., Costa A. C. (2004) Experimental parameters affecting the Morris water maze performance of a mouse model of Down syndrome. Behav Brain. Res. 154: 1–17PubMedCrossRefGoogle Scholar
  86. Su H. L., Li S. S. (2002) Molecular features of human ubiquitin-like SUMO genes and their encoded proteins. Gene 296: 65–73PubMedCrossRefGoogle Scholar
  87. Subramanian L., Benson M. D., Iniguez-Lluhi J. A. (2003) A synergy control motif within the attenuator domain of CCAAT/enhancer-binding protein alpha inhibits transcriptional synergy through its PIASy-enhanced modification by SUMO-1 or SUMO-3. J. Biol. Chem. 278: 9134–9141PubMedCrossRefGoogle Scholar
  88. Swatton J. E., Sellers L. A., Faull R. L., Holland A., Iritani S., Bahn S. (2004) Increased MAP kinase activity in Alzheimer’s and Down syndrome but not in schizophrenia human brain. Eur. J. Neurosci. 19: 2711–2719PubMedCrossRefGoogle Scholar
  89. Sweatt J. D. (2001) The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J. Neurochem. 76: 1–10PubMedCrossRefGoogle Scholar
  90. Sweatt J. D., Weeber E. J. (2003) Genetics of childhood disorders: LII. Learning and memory, part 5: human cognitive disorders and the ras/ERK/CREB pathway. J. Am. Acad. Child Adolesc. Psychiatry 42: 873–876PubMedCrossRefGoogle Scholar
  91. Tao X., Finkbeiner S., Arnold D. B., Shaywitz A. J., Greenberg M. E. (1998) 2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron. 20: 709–726PubMedCrossRefGoogle Scholar
  92. Teyssier C., Belguise K., Galtier F., Cavailles V., Chalbos D. (2003) Receptor-interacting protein 140 binds c-Jun and inhibits estradiol-induced activator protein-1 activity by reversing glucocorticoid receptor-interacting protein 1 effect. Mol. Endocrinol. 17: 287–299PubMedCrossRefGoogle Scholar
  93. Thomas G. M., Huganir R. L. (2004) MAPK cascade signalling and synaptic plasticity. Nat. Rev. Neurosci. 5: 173–183PubMedCrossRefGoogle Scholar
  94. Vanhoutte P., Nissen J. L., Brugg B., Gaspera B. D., Besson M. J., Hipskind R. A., Caboche J. (2001) Opposing roles of Elk-1 and its brain-specific isoform, short Elk-1, in nerve growth factor-induced PC12 differentiation. J. Biol. Chem. 276: 5189–5196PubMedCrossRefGoogle Scholar
  95. Vickers E. R., Kasza A., Kurnaz I. A., Seifert A., Zeef L. A., O’donnell A., Hayes A., Sharrocks A. D. (2004) Ternary complex factor-serum response factor complex-regulated gene activity is required for cellular proliferation and inhibition of apoptotic cell death. Mol Cell Biol. 24: 10340–10351PubMedCrossRefGoogle Scholar
  96. Wang, J. C., Derynck, M. K., Nonaka, D. F., Khodabakhsh, D. B., Haqq, C., and Yamamoto, K. R. (2004). Chromatin immunoprecipitation (ChIP) scanning identifies primary glucocorticoid receptor target genes. Proc. Natl. Acad. Sci. USA. 101:15603–15608Google Scholar
  97. Wang G. L., Timchenko N. A. (2005) Dephosphorylated C/EBPalpha accelerates cell proliferation through sequestering retinoblastoma protein. Mol. Cell Biol. 25: 1325–1338PubMedCrossRefGoogle Scholar
  98. Watanabe H., Sawada J., Yano K., Yamaguchi K., Goto M., Handa H. (1993) cDNA cloning of transcription factor E4TF1 subunits with Ets and notch motifs. Mol. Cell Biol. 13: 1385–1391PubMedGoogle Scholar
  99. West A. E., Chen W. G., Dalva M. B., Dolmetsch R. E., Kornhauser J. M., Shaywitz A. J., Takasu M. A., Tao X., Greenberg M. E. (2001) Calcium regulation of neuronal gene expression. Proc. Natl. Acad. Sci. USA. 98: 11024–11031PubMedCrossRefADSGoogle Scholar
  100. Wise P. M. (2002) Estrogens and neuroprotection. Trends Endocrinol. Metab. 13: 229–230PubMedCrossRefGoogle Scholar
  101. Woods Y. L., Rena G., Morrice N., Barthel A., Becker W., Guo S., Unterman T. G., Cohen P. (2001) The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site. Biochem. J. 355: 597–607PubMedGoogle Scholar
  102. Yang E. J., Ahn Y. S., Chung K. C. (2001) Protein kinase Dyrk1 activates cAMP response element-binding protein during neuronal differentiation in hippocampal progenitor cells. J. Biol. Chem. 276: 39819–39824PubMedCrossRefGoogle Scholar
  103. Yang S. H., Jaffray E., Hay R. T., Sharrocks A. D. (2003) Dynamic interplay of the SUMO and ERK pathways in regulating Elk-1 transcriptional activity. Mol. Cell 12: 63–74PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  1. 1.Eleanor Roosevelt Institute at the University of DenverDenverUSA
  2. 2.Department of Biochemistry and Molecular GeneticsUniversity of Colorado Health Sciences CenterAuroraUSA
  3. 3.Eleanor Roosevelt Institute at the University of DenverDenverUSA

Personalised recommendations