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Dyrk1a activates antioxidant NQO1 expression through an ERK1/2-Nrf2 dependent mechanism

Christophe Noll1, Asma Tlili, Clémentine Ripoll

  • 1Univ Paris Diderot-CNRS EAC 4413, Unit of Functional and Adaptive Biology (BFA), Case 7104, 75205 Paris cedex 13, France.

Molecular Genetics and Metabolism
|December 20, 2011
PubMed
Abstract

Insights

Overexpression of DYRK1A kinase in mice increases nuclear NRF2 levels, linking DYRK1A to the NRF2 signaling pathway. This kinase influences homocysteine metabolism and cardiovascular risk factors.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Genetics

Background:

  • Down syndrome is associated with lower plasma homocysteine levels.
  • DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1a) is implicated in homocysteine metabolism regulation.
  • DYRK1A overexpression in mice lowers plasma homocysteine via increased hepatic S-adenosyhomocysteine hydrolase (SAHH) activity, dependent on NAD(P)H:quinone oxidoreductase-1 (NQO1).

Purpose of the Study:

  • To investigate the effect of DYRK1A overexpression on NRF2 and AhR signaling pathways in mice.
  • To elucidate the molecular mechanisms linking DYRK1A to homocysteine metabolism.

Main Methods:

  • Examined effects of DYRK1A overexpression in mice using real-time quantitative reverse-transcription polymerase reaction and western blotting.
  • Analyzed NRF2 and AhR signaling pathway activation in liver tissue.

Main Results:

  • DYRK1A overexpression increased nuclear NRF2 quantity and activated ERK1/2 signaling.
  • No significant effect of DYRK1A overexpression was observed on PI3K/AKT activation or the AhR signaling pathway in mouse liver.
  • Harmine, an inhibitor, was used to study DYRK1A effects.

Conclusions:

  • DYRK1A is linked to the NRF2 signaling pathway.
  • This study reveals a novel connection between DYRK1A and NRF2 activation, impacting homocysteine metabolism.

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