Abstract
The Cdc25A phosphatase positively regulates cell-cycle transitions, is degraded by the proteosome throughout interphase and in response to stress, and is overproduced in human cancers. The kinases targeting Cdc25A for proteolysis during early cell-cycle phases have not been identified, and mechanistic insight into the cause of Cdc25A overproduction in human cancers is lacking. Here, we demonstrate that glycogen synthase kinase-3beta (GSK-3beta) phosphorylates Cdc25A to promote its proteolysis in early cell-cycle phases. Phosphorylation by GSK-3beta requires priming of Cdc25A, and this can be catalyzed by polo-like kinase 3 (Plk-3). Importantly, a strong correlation between Cdc25A overproduction and GSK-3beta inactivation was observed in human tumor tissues, indicating that GSK-3beta inactivation may account for Cdc25A overproduction in a subset of human tumors.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Cycle / radiation effects
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Cell Line, Tumor
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Checkpoint Kinase 1
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Enzyme Activation / radiation effects
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Enzyme Stability / radiation effects
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Gene Expression Regulation, Neoplastic*
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Glycogen Synthase Kinase 3 / metabolism*
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Glycogen Synthase Kinase 3 beta
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Humans
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Mice
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Models, Biological
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Neoplasms / enzymology*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / radiation effects
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Phosphoserine / metabolism
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Phosphothreonine / metabolism
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Protein Binding / radiation effects
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Protein Kinases / metabolism
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Protein Processing, Post-Translational* / radiation effects
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Radiation, Ionizing
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Ubiquitin / metabolism*
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beta-Transducin Repeat-Containing Proteins / metabolism
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cdc25 Phosphatases / metabolism*
Substances
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Ubiquitin
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beta-Transducin Repeat-Containing Proteins
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Phosphothreonine
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Phosphoserine
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Protein Kinases
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Phosphatidylinositol 3-Kinases
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Checkpoint Kinase 1
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Glycogen Synthase Kinase 3
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cdc25 Phosphatases