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Pten regulates Aurora-A and cooperates with Fbxw7 in modulating radiation-induced tumor development.

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.

Pubmed ID: 22513362


  • Kwon YW
  • Kim IJ
  • Wu D
  • Lu J
  • Stock WA
  • Liu Y
  • Huang Y
  • Kang HC
  • DelRosario R
  • Jen KY
  • Perez-Losada J
  • Wei G
  • Balmain A
  • Mao JH


Molecular cancer research : MCR

Publication Data

June 19, 2012

Associated Grants

  • Agency: NCI NIH HHS, Id: R01 CA116481
  • Agency: NCI NIH HHS, Id: R01 CA116481
  • Agency: NCI NIH HHS, Id: U01 CA141455

Mesh Terms

  • Animals
  • Aurora Kinase A
  • Aurora Kinases
  • Binding Sites
  • Blotting, Western
  • Cell Line
  • F-Box Proteins
  • Female
  • Gamma Rays
  • Glycogen Synthase Kinase 3
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • NIH 3T3 Cells
  • Neoplasms, Radiation-Induced
  • PTEN Phosphohydrolase
  • Protein Binding
  • Protein-Serine-Threonine Kinases
  • Time Factors
  • Ubiquitin
  • Ubiquitin-Protein Ligases