American Association for Cancer Research
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Supplementary Table 1, Figures 1-3 from Pten Regulates Aurora-A and Cooperates with Fbxw7 in Modulating Radiation-Induced Tumor Development

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journal contribution
posted on 2023-04-03, 17:43 authored by 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

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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. Mol Cancer Res; 10(6); 834–44. ©2012 AACR.

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