Other
14 Authors
- Kang HC,
- Kim IJ,
- Wei G,
- Mao JH,
- Wu D,
- Stock WA Jr,
- Liu Y,
- Lu J,
- Jen KY,
- Huang Y,
- Kwon YW,
- Balmain A,
- Perez-Losada J,
- DelRosario R
| First Author | Kwon YW | Year | 2012 |
| Journal | Mol Cancer Res | Volume | 10 |
| Issue | 6 | Pages | 834-44 |
| PubMed ID | 22513362 | Mgi Jnum | J:205391 |
| Mgi Id | MGI:5544710 | Doi | 10.1158/1541-7786.MCR-12-0025 |
| Citation | Kwon YW, et al. (2012) Pten regulates Aurora-A and cooperates with Fbxw7 in modulating radiation-induced tumor development. Mol Cancer Res 10(6):834-44 |
| abstractText | 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 GSK3beta. Using a series of truncated Aurora-A proteins and site-directed mutagenesis, we identified distinct FBXW7 and GSK3beta-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/GSK3beta 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. |
