Abstract
Pten-/- cells display a partially defective checkpoint in response to ionizing radiation (IR). The checkpoint defect was traced to the ability of AKT to phosphorylate CHK1 at serine 280, since a nonphosphorylated mutant of CHK1 (S280A) complemented the checkpoint defect and restored CDC25A degradation. CHK1 phosphorylation at serine 280 led to covalent binding of 1 to 2 molecules of ubiquitin and cytoplasmic CHK1 localization. Primary breast carcinomas lacking PTEN expression and having elevated AKT phosphorylation had increased cytoplasmic CHK1 and displayed aneuploidy (p <0.005). We conclude that loss of PTEN and subsequent activation of AKT impair CHK1 through phosphorylation, ubiquitination, and reduced nuclear localization to promote genomic instability in tumor cells.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Breast Neoplasms / metabolism
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Cell Line
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Cell Line, Tumor
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Checkpoint Kinase 1
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Cytoplasm / metabolism
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DNA Damage
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Embryo, Mammalian / cytology
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G2 Phase
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Growth Substances / metabolism
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Humans
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Mice
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Mice, Knockout
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Mice, Transgenic
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Models, Biological
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Models, Genetic
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Mutation
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Phosphoric Monoester Hydrolases / metabolism
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Phosphorylation
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Plasmids / metabolism
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Protein Kinases / genetics*
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Protein Kinases / physiology*
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Radiation, Ionizing
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Serine / chemistry
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Signal Transduction
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Stem Cells / cytology
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Time Factors
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Ubiquitin / metabolism
Substances
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Growth Substances
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Proto-Oncogene Proteins
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Ubiquitin
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Serine
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Protein Kinases
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AKT1 protein, human
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CHEK1 protein, human
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Checkpoint Kinase 1
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Chek1 protein, mouse
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Phosphoric Monoester Hydrolases