Two key genes closely implicated with the neuropathological characteristics in Down syndrome: DYRK1A and RCAN1

Park, Joongkyu; Oh, Yohan; Chung, Kwang Chul

doi:10.5483/bmbrep.2009.42.1.006

Cited by 72 publications

(50 citation statements)

References 95 publications

(122 reference statements)

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“…Chromosome 21 contains the genes for regulator of calcineurin 1 (RCAN1) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A); RCAN1 is an endogenous feedback regulator of Cn activity that facilitates activity at low levels but restrains Cn at higher levels to mitigate the effects of oxidative and calcium stress (26 ). DYRK1A phosphorylates NFAT, thereby mediating its nuclear export (27 ). The increase in the production of these 2 proteins has been suggested to lead to NFAT dysregulation and could explain many of the features of Down syndrome (28 ).…”

Section: Brainmentioning

confidence: 99%

Molecular Diagnostics of Calcineurin-Related Pathologies

Musson

Cobbaert²,

Smit³

2012

Clinical Chemistry

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BACKGROUND The Ca2+-dependent protein phosphatase enzyme calcineurin (Cn) (protein phosphatase 3) is best known for its role as director of the adaptive immune response. One of its principal substrates is the nuclear factor of activated T cells (NFAT), which translocates to the nucleus after dephosphorylation to mediate gene transcription. Drugs targeting Cn (the Cn inhibitors tacrolimus and cyclosporin A) have revolutionized posttransplantation therapy in allograft recipients by considerably reducing rejection rates. CONTENT Owing primarily to intensive study of the side effects of the Cn inhibitors, the unique importance of Cn and Cn/NFAT signaling in the normal physiological processes of many other cell and tissue types is becoming more evident. During the last decade, it has become clear that an extensive and diverse array of clinical conditions can be traced back, at least in part, to a disturbed Cn-signaling axis. Hence, both diagnostics and therapeutic monitoring could benefit from a technique that conveniently reads out Cn/NFAT operative status. SUMMARY This review outlines the current knowledge on the pathologic conditions that have calcineurin as a common denominator and reports on the progress that has been made toward successfully applying Cn and Cn/NFAT activity markers in molecular diagnostics.

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Section: Brainmentioning

confidence: 99%

Molecular Diagnostics of Calcineurin-Related Pathologies

Musson

Cobbaert²,

Smit³

2012

Clinical Chemistry

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“…Dual-specificity tyrosine-(Y) phosphorylation-regulated kinase 1A (Dyrk1A), one of the DSCR genes, encodes a proline-directed serine/threonine kinase, which phosphorylates several transcription factors, including NFAT, CREB, and FKHR (11,12). DYRK1A transgenic (Tg) mice, which express human DYRK1A present on a bacterial artificial chromosome, exhibit significant impairment in hippocampal-dependent memory tasks and altered synaptic plasticity, features that are similar to those seen in DS patients (13).…”

Section: Down Syndrome (Ds)mentioning

confidence: 99%

Dyrk1A Phosphorylates p53 and Inhibits Proliferation of Embryonic Neuronal Cells

Park

Yoo

et al. 2010

Journal of Biological Chemistry

109

106

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Down syndrome (DS) is associated with many neural defects, including reduced brain size and impaired neuronal proliferation, highly contributing to the mental retardation. Those typical characteristics of DS are closely associated with a specific gene group "Down syndrome critical region" (DSCR) on human chromosome 21. Here we investigated the molecular mechanisms underlying impaired neuronal proliferation in DS and, more specifically, a regulatory role for dual-specificity tyrosine-(Y) phosphorylation-regulated kinase 1A (Dyrk1A), a DSCR gene product, in embryonic neuronal cell proliferation. We found that Dyrk1A phosphorylates p53 at Ser-15 in vitro and in immortalized rat embryonic hippocampal progenitor H19-7 cells. In addition, Dyrk1A-induced p53 phosphorylation at Ser-15 led to a robust induction of p53 target genes (e.g. p21 CIP1 ) and impaired G 1 /G 0 -S phase transition, resulting in attenuated proliferation of H19-7 cells and human embryonic stem cellderived neural precursor cells. Moreover, the point mutation of p53-Ser-15 to alanine rescued the inhibitory effect of Dyrk1A on neuronal proliferation. Accordingly, brains from embryonic DYRK1A transgenic mice exhibited elevated levels of Dyrk1A, Ser-15 (mouse Ser-18)-phosphorylated p53, and p21 CIP1 as well as impaired neuronal proliferation. These findings suggest that up-regulation of Dyrk1A contributes to altered neuronal proliferation in DS through specific phosphorylation of p53 at Ser-15 and subsequent p21 CIP1 induction. Down syndrome (DS)2 is the most common genetic disorder and is caused by the presence of all or part of an extra human chromosome 21 (1). The patients have many abnormalities such as mental retardation, deficits in learning and memory, and early onset Alzheimer disease (AD) (2, 3). The brains of DS patients exhibit an arrest of neurogenesis in many CNS regions, including the hippocampus at all ages, even the fetal stage (4 -6). Cell proliferation has been shown to be impaired in human fetal DS brains and Ts65Dn mouse brains (7,8). Ts65Dn mouse possesses an extra copy of a part of chromosome 16, which corresponds to human chromosome 21, and also shows learning and memory impairments and altered neuronal proliferation in the hippocampus (8 -10). However, the molecular mechanisms underlying impaired neuronal proliferation in DS are unknown.The typical characteristics of DS are thought to be closely associated with a gene group mapped to a specific region of human chromosome 21q22 "Down syndrome critical region" (DSCR) (3). Dual-specificity tyrosine-(Y) phosphorylation-regulated kinase 1A (Dyrk1A), one of the DSCR genes, encodes a proline-directed serine/threonine kinase, which phosphorylates several transcription factors, including NFAT, CREB, and FKHR (11, 12). DYRK1A transgenic (Tg) mice, which express human DYRK1A present on a bacterial artificial chromosome, exhibit significant impairment in hippocampal-dependent memory tasks and altered synaptic plasticity, features that are similar to those seen in DS patients (13). Several ot...

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“…Dyrk1A is a dual specificity protein kinase that is activated by autophosphorylation on a tyrosine residue in the activation loop, and it phosphorylates serine or threonine residues in substrate proteins (1). Dyrk1A is a multifunctional protein kinase with various substrates, such as transcription factors, splicing factors, and synapse-associated proteins (2,3). Dyrk1A contains a nuclear localization sequence at its N terminus and locates both to the cytosol and nucleus, phosphorylating nuclear and cytoplasmic substrate proteins.…”

mentioning

confidence: 99%