Dyrk1A phosphorylates p53 and inhibits proliferation of embryonic neuronal cells.
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.
Park
Joongkyu
J
Department of Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
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
D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004622:Embryo, Mammalian / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000097603:Dyrk Kinases
D050759:Cyclin-Dependent Kinase Inhibitor p21; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; D000097603:Dyrk Kinases; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; C495901:TP53 protein, human