Send to

Choose Destination
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

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


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.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center