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

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.
Mesh Terms:
Apoptosis, Cell Cycle Proteins, Cell Line, Tumor, Cell Nucleus, Cysteine Proteinase Inhibitors, DNA Damage, DNA-Binding Proteins, Doxorubicin, Etoposide, Humans, Immunohistochemistry, Immunoprecipitation, In Situ Nick-End Labeling, Leupeptins, Phosphorylation, Protein Binding, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-mdm2, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Ubiquitination
J. Biol. Chem.
Date: Feb. 12, 2010
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