Regulation of the proapoptotic activity of huntingtin interacting protein 1 by Dyrk1 and caspase-3 in hippocampal neuroprogenitor cells

J Neurosci Res. 2005 Jul 1;81(1):62-72. doi: 10.1002/jnr.20534.

Abstract

Dual specific protein kinase Dyrks are thought to play a key role in the regulation of cell growth in a variety of cellular systems. Interestingly, human Dyrk1 is mapped to the Down's syndrome (DS) critical region on chromosome 21, and thought to be a candidate gene responsible for the mental retardation of DS patients. Huntingtin-interacting protein 1 (Hip-1), a proapoptotic mediator, is implicated as a molecular accomplice in the pathogenesis of Huntington's disease. In the present study we found that Dyrk1 selectively binds to and phosphorylates Hip-1 during the neuronal differentiation of embryonic hippocampal neuroprogenitor (H19-7) cells. The Dyrk1-mediated phosphorylation of Hip-1, in response to bFGF, resulted in the blockade of Hip-1-mediated neuronal cell death as well as the enhancement of neurite outgrowth. Furthermore, the addition of etoposide to proliferating H19-7 cells caused the diminished binding of Hip-1 to Dyrk1 and the levels of phosphorylated Hip-1 remarkably decreased. Simultaneously, the dissociated Hip-1 from Dyrk1 bound to caspase-3 in response to etoposide, which led to its activation and consequently cell death in H19-7 cells. These data suggest that the phosphorylation of Hip-1 by Dyrk1 has a dual role in regulating neuronal differentiation and cell death. The interaction between Dyrk1 and Hip-1 appeared to be differentially modulated by different kinds of stimuli, such as bFGF and etoposide in H19-7 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Caspase 3
  • Caspases / physiology*
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology
  • Cell Line
  • DNA-Binding Proteins / metabolism*
  • Etoposide / pharmacology
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Neurons / drug effects
  • Neurons / metabolism*
  • Nucleic Acid Synthesis Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases / physiology*
  • Protein-Tyrosine Kinases
  • Rats
  • Stem Cells / cytology
  • Stem Cells / drug effects
  • Stem Cells / metabolism*

Substances

  • DNA-Binding Proteins
  • HIP1 protein, human
  • Nucleic Acid Synthesis Inhibitors
  • Etoposide
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • CASP3 protein, human
  • Casp3 protein, rat
  • Caspase 3
  • Caspases