Abstract
The DNA damage response is coordinated by phosphatidylinositol 3-kinase-related kinases, ATM, ATR, and DNA-PK. SMG-1 is the least studied stress-responsive member of this family. Here, we show that SMG-1 regulates the G 1/S checkpoint through both a p53-dependent, and a p53-independent pathway. We identify Cdc25A as a new SMG-1 substrate, and show that cells depleted of SMG-1 exhibit prolonged Cdc25A stability, failing to inactivate CDK2 in response to radiation. Given an increased tumor growth following depletion of SMG-1, our data demonstrate a novel role for SMG-1 in regulating Cdc25A and suppressing oncogenic CDK2 driven proliferation, confirming SMG-1 as a tumor suppressor.
Keywords:
CDK2; Cdc25A; G1/S checkpoint; SMG-1; cell cycle; p53; tumor suppressor; tumorigenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Movement / drug effects
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Cyclin-Dependent Kinase 2 / genetics
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Cyclin-Dependent Kinase 2 / metabolism*
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G1 Phase Cell Cycle Checkpoints / genetics
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Gene Expression
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Humans
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Neoplasms / metabolism*
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphorylation
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Phosphotransferases / metabolism*
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Protein Serine-Threonine Kinases
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S Phase Cell Cycle Checkpoints / genetics
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Signal Transduction
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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cdc25 Phosphatases / genetics
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cdc25 Phosphatases / metabolism*
Substances
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Tumor Suppressor Protein p53
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Phosphotransferases
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Protein Serine-Threonine Kinases
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SMG1 protein, human
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CDK2 protein, human
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Cyclin-Dependent Kinase 2
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CDC25A protein, human
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cdc25 Phosphatases