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Dyrk1A phosphorylates p53 and inhibits proliferation of embryonic neuronal cells

Joongkyu Park1, Yohan Oh, Lang Yoo

  • 1Department of Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.

The Journal of Biological Chemistry
|August 11, 2010
PubMed

Insights

Dual-specificity tyrosine-(Y) phosphorylation-regulated kinase 1A (Dyrk1A) up-regulation impairs embryonic neuronal proliferation in Down syndrome (DS). Dyrk1A phosphorylates p53, inhibiting cell cycle progression and reducing neural precursor cell proliferation.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Down syndrome (DS) is characterized by neural defects, including reduced brain size and impaired neuronal proliferation, linked to the Down syndrome critical region (DSCR) on chromosome 21.
  • Dual-specificity tyrosine-(Y) phosphorylation-regulated kinase 1A (Dyrk1A) is a gene product within the DSCR implicated in neural development.

Purpose of the Study:

  • To investigate the molecular mechanisms of impaired neuronal proliferation in Down syndrome.
  • To elucidate the specific role of Dyrk1A in regulating embryonic neuronal cell proliferation.

Main Methods:

  • In vitro and cellular assays using immortalized rat embryonic hippocampal progenitor H19-7 cells and human embryonic stem cell-derived neural precursor cells.
  • Investigated the phosphorylation of p53 by Dyrk1A and the subsequent effects on cell cycle progression and gene expression.
  • Utilized transgenic DYRK1A mouse models to examine in vivo effects.

Main Results:

  • Dyrk1A was found to phosphorylate p53 at Ser-15, leading to the induction of p53 target genes like p21(CIP1).
  • This phosphorylation event inhibited the G(1)/G(0)-S phase transition, resulting in attenuated proliferation of both H19-7 cells and human neural precursor cells.
  • A point mutation of p53-Ser-15 to alanine rescued the inhibitory effect of Dyrk1A on neuronal proliferation.
  • Embryonic brains of DYRK1A transgenic mice showed elevated Dyrk1A, phosphorylated p53 (Ser-18), and p21(CIP1), alongside impaired neuronal proliferation.

Conclusions:

  • Up-regulation of Dyrk1A contributes to altered neuronal proliferation in Down syndrome.
  • The mechanism involves specific phosphorylation of p53 at Ser-15, leading to p21(CIP1) induction and cell cycle arrest.
  • Dyrk1A is a key molecular player in the neurodevelopmental abnormalities observed in Down syndrome.

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