Function and regulation of Dyrk1A: towards understanding Down syndrome

Park, Joongkyu; Song, Woo-Joo; Chung, Kwang Chul

doi:10.1007/s00018-009-0123-2

Cited by 180 publications

(151 citation statements)

References 67 publications

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“…71 Most likely, DYRK1A is regulated at the protein level, and the balance of DYRK1A level is thus vitally important for neurodevelopment. 72,73 Because miR-1246 in response to active p53 can bind to DYRK1A mRNA and inhibit its translation, consequently reducing the protein level of DYRK1A as described above, 20 we speculate that the downregulation of DYRK1A level by p53 or p73 via miR-1246 might play a role in restricting Down syndrome development while also preventing cancer formation. Consistent with this conjecture is a good correlation between the lifespan of Down syndrome patients and the status of p53 single nucleotide polymorphism (SNP).…”

Section: Role Of the P53-mir-1246-dyrk1a-nfat Pathway In Down Syndromementioning

confidence: 86%

MiR-1246: A new link of the p53 family with cancer and Down syndrome

et al. 2012

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Section: Role Of the P53-mir-1246-dyrk1a-nfat Pathway In Down Syndromementioning

confidence: 86%

MiR-1246: A new link of the p53 family with cancer and Down syndrome

et al. 2012

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“…We also propose that diminished Hap1-Dcaf7 interaction is a likely mechanism for DYRK1A-mediated growth retardation in DS. Downregulating DYRK1A levels might not be an ideal solution, because DYRK1A acts on a large number of substrate proteins, including transcription factors, splicing factors, and synaptic proteins (42). If the level of Hap1-Dcaf7 interaction indeed mediates the function of Hap1 in food intake, enhancement of this interaction by up-regulating either Hap1 or Dcaf7 could provide promising therapeutic options for treating stunted growth in DS and other growth disorders.…”

Section: Discussionmentioning

confidence: 99%

“…The increased DYRK1A level in the Hap1-KO mouse brain was particularly interesting because DYRK1A also is overexpressed in the brains of individuals with DS, and this overexpression may explain some of the neuropathological traits of this syndrome (22,42). To validate the competition between Hap1 and DYRK1A for binding with Dcaf7 in a different and more disease-relevant model, we examined the association of Hap1 and Dcaf7 in a DS mouse model, Ts65Dn, which carries a partial trisomy of mouse chromosome 21, including the DYRK1A gene (43,44).…”

Section: Hap1 Stabilizes the Protein Level Of Dcaf7 By Inhibiting Itsmentioning

confidence: 99%

DYRK1A regulates Hap1–Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome

Xiang

Ning

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Huntingtin-associated protein 1 (Hap1) is known to be critical for postnatal hypothalamic function and growth. Hap1 forms stigmoid bodies (SBs), unique neuronal cytoplasmic inclusions of unknown function that are enriched in hypothalamic neurons. Here we developed a simple strategy to isolate the SB-enriched fraction from mouse brain. By analyzing Hap1 immunoprecipitants from this fraction, we identified a Hap1-interacting SB component, DDB1 and CUL4 associated factor 7 (Dcaf7)/WD40 repeat 68 (WDR68), whose protein level and nuclear translocation are regulated by Hap1. Moreover, we found that Hap1 bound Dcaf7 competitively in cytoplasm with dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a protein implicated in Down syndrome (DS). Depleting Hap1 promoted the DYRK1A-Dcaf7 interaction and increased the DYRK1A protein level. Transgenic DS mice overexpressing DYRK1A showed reduced Hap1-Dcaf7 association in the hypothalamus. Furthermore, the overexpression of DYRK1A in the hypothalamus led to delayed growth in postnatal mice, suggesting that DYRK1A regulates the Hap1-Dcaf7 interaction and postnatal growth and that targeting Hap1 or Dcaf7 could ameliorate growth retardation in DS.H untingtin-associated protein 1 (Hap1) is a cytoplasmic protein highly expressed in neurons of the CNS (1, 2). Hap1 was initially recognized for its binding to polyglutamine-expanded huntingtin (Htt), the protein responsible for Huntington's disease (3). Because Hap1 is expressed at various levels in different types of neurons (1,(4)(5)(6)(7)(8), it is likely involved in cell type-specific functions of the brain. For example, Hap1 is abundantly expressed in the hypothalamus, and its expression in the hypothalamus influences the central control of feeding (9); as a direct result, mice lacking Hap1 are malnourished and die in the early postnatal period (5, 10, 11). The function of Hap1 is also age dependent and appears to be important for postnatal neurogenesis in the paraventricular nuclei, the lateral hypothalamus (5, 11), and the dentate gyrus of the hippocampus (7).The specific function of Hap1 in the hypothalamus may be associated with unique cytoplasmic structures called "stigmoid bodies" (SBs), which are formed by Hap1 in the hypothalamus (12, 13) and appear to be non-membrane-bound, ovoid to circular in shape, and 0.5-3 μm in diameter (14,15). Widely regarded as a determinant marker for SBs, Hap1 is capable of sequestering several important disease-related proteins into SB-like inclusions in cell cultures, including Abelson helper integration site 1 (Ahi1), androgen receptor, TBP, and ataxin-3 (6, 16-18). However, in vivo evidence for such sequestration exists only for Ahi1, which is responsible for specific forms of Joubert syndrome. Other proteins, such as SorLA/LR11, sortilin, 5-HT 7 receptor, and 14-3-3, are also reported to be associated with . Although SBs are abundant in the hypothalamus, their functions remain elusive, despite speculation that they might be involved in sex-steroid maturation (15). We bel...

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“…Furthermore, Dyrk1A-mediated phosphorylation of p53 would not be the only one cause of impaired neuronal proliferation in DS, because Dyrk1A has a lot of substrates involved in various cellular processes (42). For example, nuclear factor of activated T cells (NFAT) inhibition by Dyrk1A phosphorylation could contribute to the altered proliferation (51,52).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, Dyrk1A dosage imbalance reduces neuron-restrictive silencer factor (NRSF/REST) levels and deregulates chromosomal clusters of genes located near NRSF/REST-binding sites, suggesting that Dyrk1A overexpression may perturb overall gene expression (53,54). Dyrk1A is also known to phosphorylate proteins associated with mRNA splicing (Cyclin L2, SF2, and SF3) and translation (eIF2B⑀) (42). Interestingly, Yabut et al recently reported that transiently overexpressed Dyrk1A by in utero electroporation inhibits neural cell proliferation in embryonic mouse neocortex, in which the nuclear export and degradation of cyclin D1 could act as a key cell cycle modulator (41).…”

Section: Discussionmentioning

confidence: 99%

Dyrk1A Phosphorylates p53 and Inhibits Proliferation of Embryonic Neuronal Cells

Park

Yoo

et al. 2010

Journal of Biological Chemistry

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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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Function and regulation of Dyrk1A: towards understanding Down syndrome

Cited by 180 publications

References 67 publications

MiR-1246: A new link of the p53 family with cancer and Down syndrome

MiR-1246: A new link of the p53 family with cancer and Down syndrome

DYRK1A regulates Hap1–Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome

Dyrk1A Phosphorylates p53 and Inhibits Proliferation of Embryonic Neuronal Cells

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