title: Pten regulates Aurora-A and cooperates with Fbxw7 in modulating radiation-induced tumor development.
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.
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, CA 94720, USA.
authors.forename: Yong-Won
authors.initials: YW
authors.lastname: Kwon
authors.forename: Il-Jin
authors.initials: IJ
authors.lastname: Kim
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.forename: William A
authors.initials: WA
authors.lastname: Stock
authors.forename: Yueyong
authors.initials: Y
authors.lastname: Liu
authors.forename: Yurong
authors.initials: Y
authors.lastname: Huang
authors.forename: Hio Chung
authors.initials: HC
authors.lastname: Kang
authors.forename: Reyno
authors.initials: R
authors.lastname: DelRosario
authors.forename: Kuang-Yu
authors.initials: KY
authors.lastname: Jen
authors.forename: Jesus
authors.initials: J
authors.lastname: Perez-Losada
authors.forename: Guangwei
authors.initials: G
authors.lastname: Wei
authors.forename: Allan
authors.initials: A
authors.lastname: Balmain
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Mao
mesh_terms: D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D002460:Cell Line; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D005720:Gamma Rays; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D041681:NIH 3T3 Cells; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513272:Fbxw7 protein, mouse; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D017346:Protein Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse