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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Apoptosis / genetics*
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Line, Tumor
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Cell Nucleus / metabolism*
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Cysteine Proteinase Inhibitors / toxicity
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DNA Damage / genetics
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DNA Damage / physiology*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Doxorubicin / toxicity
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Dyrk Kinases
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Etoposide / toxicity
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Humans
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Immunohistochemistry
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Immunoprecipitation
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In Situ Nick-End Labeling
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Leupeptins / toxicity
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Phosphorylation / drug effects
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Protein Binding / drug effects
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Protein Binding / genetics
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins c-mdm2 / genetics
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Proto-Oncogene Proteins c-mdm2 / metabolism*
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Ubiquitination / genetics
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Ubiquitination / physiology
Substances
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Cell Cycle Proteins
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Cysteine Proteinase Inhibitors
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DNA-Binding Proteins
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Leupeptins
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Etoposide
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Doxorubicin
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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Protein-Tyrosine Kinases
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde