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

Yong Won Kwon, Il Jin Kim, Di Wu, Jing Lu, William A. Stock, Yueyong Liu, Yurong Huang, Hio Chung Kang, Reyno DelRosario, Kuang-Yu Jen, Jesus Perez-Losada, Guangwei Wei, Allan Balmain, Jian Hua Mao

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)834-844
Number of pages11
JournalMolecular Cancer Research
Volume10
Issue number6
DOIs
StatePublished - Jun 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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