title: 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.
abstract: 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.
authors.affiliation: Eleanor Roosevelt Institute at the University of Denver, CO 80045, USA. kgardine@du.edu
authors.forename: Katheleen
authors.initials: K
authors.lastname: Gardiner
mesh_terms: D002874:Chromosome Mapping; D002891:Chromosomes, Human, Pair 21; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics*; D004314:Down Syndrome / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D007700:Kinetics; D011499:Protein Processing, Post-Translational; D011960:Receptors, Estrogen / Q000235:genetics*; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D014158:Transcription, Genetic; D050807:ets-Domain Protein Elk-1 / Q000235:genetics*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D050807:ets-Domain Protein Elk-1