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Title

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

AuthorsKwon, Yong-Won; DelRosario, Reyno; Pérez-Losada, J. ; Mao, Jian-Hua
Issue Date2012
PublisherAmerican Association for Cancer Research
CitationMolecular Cancer Research 10: 834-844 (2012)
AbstractThe 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. ©2012 AACR.
DescriptionPMCID: PMC3388112.-- et al.
Publisher version (URL)http://dx.doi.org/10.1158/1541-7786.MCR-12-0025
URIhttp://hdl.handle.net/10261/62798
DOI10.1158/1541-7786.MCR-12-0025
Identifiersissn: 1541-7786
e-issn: 1557-3125
Appears in Collections:(IBMCC) Artículos
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