Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ethanol exposure during development is teratogenic. The central nervous system (CNS) is particularly susceptible to ethanol toxicity. In fact, heavy gestational ethanol consumption is one of the leading known causes of mental retardation in the Western world. Ethanol exposure disrupts the proliferation of glia and neuronal precursors in the developing CNS. Depending upon cell population and blood ethanol concentration, ethanol can either inhibit or stimulate cell proliferation. Two features of cell proliferation that are affected by ethanol exposure are the growth fraction (the proportion of cells that is actively cycling) and the cell cycle kinetics, particularly in the length of the G1 phase of the cell cycle. Cell proliferation in the developing CNS reflects the action of positive (mitogenic growth factors) and negative (anti-proliferative factors) regulators. Increasing evidence shows that ethanol interferes with the action of growth factors. In vitro systems are a good model to investigate ethanol neurotoxicity, since the effects of ethanol on cultured cells parallel the effects of ethanol in the developing CNS. The inhibitory effects of ethanol on cell proliferation may result from interference with mitogenic growth factors (e.g., bFGF, EGF, PDGF, IGF-I). Conversely, the stimulatory effects of ethanol may result from the interference with growth inhibiting factors (e.g., TGFbeta1). Interestingly, both in vivo and in vitro studies show that proliferating neural cells display differential sensitivity to ethanol. This differential sensitivity correlates with their response to mitogenic growth factors; that is, cells that are actively regulated by mitogenic growth factors are much more susceptible to ethanol than cells that are less or unresponsive to such factors. Ethanol interference with growth factor action could occur at three levels: ligand production, receptor expression, and/or signal transduction. Thus, ethanol-induced alterations in the developing CNS that characterize fetal alcohol syndrome apparently result from alterations in the regulatory action of growth factors.
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PMID:Growth factor-mediated neural proliferation: target of ethanol toxicity. 962 17

Dual specific protein kinase Dyrks are thought to play a key role in the regulation of cell growth in a variety of cellular systems. Interestingly, human Dyrk1 is mapped to the Down's syndrome (DS) critical region on chromosome 21, and thought to be a candidate gene responsible for the mental retardation of DS patients. Huntingtin-interacting protein 1 (Hip-1), a proapoptotic mediator, is implicated as a molecular accomplice in the pathogenesis of Huntington's disease. In the present study we found that Dyrk1 selectively binds to and phosphorylates Hip-1 during the neuronal differentiation of embryonic hippocampal neuroprogenitor (H19-7) cells. The Dyrk1-mediated phosphorylation of Hip-1, in response to bFGF, resulted in the blockade of Hip-1-mediated neuronal cell death as well as the enhancement of neurite outgrowth. Furthermore, the addition of etoposide to proliferating H19-7 cells caused the diminished binding of Hip-1 to Dyrk1 and the levels of phosphorylated Hip-1 remarkably decreased. Simultaneously, the dissociated Hip-1 from Dyrk1 bound to caspase-3 in response to etoposide, which led to its activation and consequently cell death in H19-7 cells. These data suggest that the phosphorylation of Hip-1 by Dyrk1 has a dual role in regulating neuronal differentiation and cell death. The interaction between Dyrk1 and Hip-1 appeared to be differentially modulated by different kinds of stimuli, such as bFGF and etoposide in H19-7 cells.
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PMID:Regulation of the proapoptotic activity of huntingtin interacting protein 1 by Dyrk1 and caspase-3 in hippocampal neuroprogenitor cells. 1590 74

Sotos syndrome (SoS) is characterized by tall stature, characteristic craniofacial features and mental retardation. It is caused by haploinsufficiency of the NSD1 gene. In this study, our objective was to identify downstream effectors of NSD1 and to map these effectors in signaling pathways associated with growth. Genome-wide expression studies were performed on dermal fibroblasts from SoS patients with a confirmed NSD1 abnormality. To substantiate those results, phosphorylation, siRNA and transfection experiments were performed. A significant association was demonstrated with the Mitogen-Activated Protein Kinase (MAPK) pathway. Members of the fibroblast growth factor family such as FGF4 and FGF13 contributed strongly to the differential expression in this pathway. In addition, a diminished activity state of the MAPK/ERK pathway was demonstrated in SoS. The Ras Interacting Protein 1 (RASIP1) was identified to exhibit upregulated expression in SoS. It was shown that RASIP1 dose-dependently potentiated bFGF induced expression of the MAPK responsive SBE reporter providing further support for a link between NSD1 and the MAPK/ERK signaling pathway. Additionally, we demonstrated NSD1 expression in the terminally differentiated hypertrophic chondrocytes of normal human epiphyseal growth plates. In short stature syndromes such as hypochondroplasia and Noonan syndrome, the activation level of the FGF-MAPK/ERK-pathway in epiphyseal growth plates is a determining factor for statural growth. In analogy, we propose that deregulation of the MAPK/ERK pathway in SoS results in altered hypertrophic differentiation of NSD1 expressing chondrocytes and may be a determining factor in statural overgrowth and accelerated skeletal maturation in SoS.
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PMID:Sotos syndrome is associated with deregulation of the MAPK/ERK-signaling pathway. 2315 69