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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 cell-derived 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.

SUBMITTER: Park J

PROVIDER: S-EPMC2951261 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Dyrk1A phosphorylates p53 and inhibits proliferation of embryonic neuronal cells.

Park Joongkyu J Oh Yohan Y Yoo Lang L Jung Min-Su MS Song Woo-Joo WJ Lee Sang-Hun SH Seo Hyemyung H Chung Kwang Chul KC

The Journal of biological chemistry 20100809 41

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) phosphor ...[more]

PMID: 20696760

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Dyrk1A phosphorylates p53 and inhibits proliferation of embryonic neuronal cells.

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Dyrk1A phosphorylates p53 and inhibits proliferation of embryonic neuronal cells.

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