Dyrk1A Phosphorylates p53 and Inhibits Proliferation of Embryonic Neuronal Cells

Abstract

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...

DYRK1A phoshorylates histone H3 to differentially regulate the binding of HP1 isoforms and antagonize HP1‐mediated transcriptional repression

“…Several genes up-regulated by DYRK1A depletion were targets of transcription factors negatively regulated by DYRK1A-mediated phosphorylation [14][15][16], including the nuclear factor of activated T cells (NFAT) targets EGR2 [17] and ID2 [18], and the p53 target BTG2 [19]. Genes down-regulated by DYRK1A depletion were largely inducible genes involved in cellular responses to stimuli and immune system processes ( Supplementary Fig S2B).…”

Genetic and Epigenetic Mechanisms in Down Syndrome Brain

“…Similarly, increased S100B levels stimulate p53 nuclear accumulation and inhibit proliferation [30]. DYRK1A has alternatively been shown to phosphorylate p53, impair G1/S phase transition and inhibit proliferation [31]. Finally, many HSA21 genes regulate neurogenesis through their effects on NGF, hedgehog, WNT, Notch and insulin signaling pathways [20].…”

Transient expression of Mnb/Dyrk1a couples cell cycle exit and differentiation of neuronal precursors by inducing p27KIP1 expression and suppressing NOTCH signaling

“…Nevertheless, the mechanism downstream of the MNB/DYRK1A kinase involved in this regulation remains to be elucidated. It has been recently reported that the overexpression of MNB/DYRK1A inhibits proliferation of neural progenitors derived from human embryonic stem cells (Park et al, 2010) and in the developing mouse cerebral cortex (Yabut et al, 2010) through p53 phosphorylation followed by induction of p53 target genes (e.g. p21 CIP1 ) (Park et al, 2010) and by the nuclear export and degradation of Cyclin D1 (Yabut et al, 2010).…”