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J Biol Chem. 2010 Feb 12;285(7):4909-19. doi: 10.1074/jbc.M109.042341. Epub 2009 Dec 4.

ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage.

Author information

1
Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8510, Japan.

Abstract

The tumor suppressor p53 is a transcription factor that regulates cell cycle, DNA repair, senescence, and apoptosis in response to DNA damage. Phosphorylation of p53 at Ser-46 is indispensable for the commitment to apoptotic cell death. A previous study has shown that upon exposure to genotoxic stress, DYRK2 translocates into the nucleus and phosphorylates p53 at Ser-46, thereby inducing apoptosis. However, less is known about mechanisms responsible for intracellular control of DYRK2. Here we show the functional nuclear localization signal at N-terminal domain of DYRK2. Under normal conditions, nuclear and not cytoplasmic DYRK2 is ubiquitinated by MDM2, resulting in its constitutive degradation. In the presence of proteasome inhibitors, we detected a stable complex of DYRK2 with MDM2 at the nucleus. Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus. These findings indicate that ATM controls stability and pro-apoptotic function of DYRK2 in response to DNA damage.

PMID:
19965871
PMCID:
PMC2836095
DOI:
10.1074/jbc.M109.042341
[Indexed for MEDLINE]
Free PMC Article

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