Abstract
The Aurora-A kinase gene is frequently amplified and/or overexpressed in a variety of human cancers, leading to major efforts to develop therapeutic agents targeting this pathway. Here, we show that Aurora-A is targeted for ubiquitination and subsequent degradation by the F-box protein FBXW7 in a process that is regulated by GSK3β. Using a series of truncated Aurora-A proteins and site-directed mutagenesis, we identified distinct FBXW7 and GSK3β-binding sites in Aurora-A. Mutation of critical residues in either site substantially disrupts degradation of Aurora-A. Furthermore, we show that loss of Pten results in the stabilization of Aurora-A by attenuating FBXW7-dependent degradation of Aurora-A through the AKT/GSK3β pathway. Moreover, radiation-induced tumor latency is significantly shortened in Fbxw7(+/-)Pten(+/-) mice as compared with either Fbxw7(+/-) or Pten(+/-) mice, indicating that Fbxw7 and Pten appear to cooperate in suppressing tumorigenesis. Our results establish a novel posttranslational regulatory network in which the Pten and Fbxw7 pathways appear to converge on the regulation of Aurora-A level.
2012 AACR
Publication types
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Research Support, N.I.H., Extramural
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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.
MeSH terms
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Animals
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Aurora Kinase A
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Aurora Kinases
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Binding Sites / genetics
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Blotting, Western
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Cell Line
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F-Box Proteins / genetics
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F-Box Proteins / metabolism*
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F-Box-WD Repeat-Containing Protein 7
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Female
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Gamma Rays
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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HCT116 Cells
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HEK293 Cells
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Humans
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mutation
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NIH 3T3 Cells
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Neoplasms, Radiation-Induced / genetics
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Neoplasms, Radiation-Induced / metabolism*
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Neoplasms, Radiation-Induced / pathology
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / metabolism*
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Protein Binding
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Time Factors
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Ubiquitin / metabolism
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
Substances
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F-Box Proteins
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F-Box-WD Repeat-Containing Protein 7
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Fbxw7 protein, mouse
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Ubiquitin
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Ubiquitin-Protein Ligases
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Aurka protein, mouse
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Aurora Kinase A
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Aurora Kinases
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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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Protein Serine-Threonine Kinases
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Glycogen Synthase Kinase 3
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PTEN Phosphohydrolase
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Pten protein, mouse