| Autor: |
Jian-Hua Mao, Allan Balmain, Guangwei Wei, Jesus Perez-Losada, Kuang-Yu Jen, Reyno DelRosario, Hio Chung Kang, Yurong Huang, Yueyong Liu, William A. Stock, Jing Lu, Di Wu, Il-Jin Kim, Yong-Won Kwon |
| Rok vydání: |
2023 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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