title: FOXL2 posttranslational modifications mediated by GSK3β determine the growth of granulosa cell tumours.
abstract: Approximately 97% of patients with ovarian granulosa cell tumours (GCTs) bear the C134W mutation in FOXL2; however, the pathophysiological mechanism of this mutation is unknown. Here we report how this mutation affects GCT development. Sequential posttranslational modifications of the C134W mutant occur where hyperphosphorylation at serine 33 (S33) by GSK3β induces MDM2-mediated ubiquitination and proteasomal degradation. In contrast, S33 of wild-type FOXL2 is underphosphorylated, leading to its SUMOylation and stabilization. This prominent hyperphosphorylation is also observed at S33 of FOXL2 in GCT patients bearing the C134W mutation. In xenograft mice, the S33 phosphorylation status correlates with the oncogenicity of FOXL2, and the inhibition of GSK3β efficiently represses GCT growth. These findings reveal a previously unidentified regulatory mechanism that determines the oncogenic attributes of the C134W mutation via differential posttranslational modifications of FOXL2 in GCT development.
authors.affiliation: 1] College of Pharmacy, Chung-Ang University, 84 Heukseok-Ro, Dongjak-Gu, Seoul 156-756, Korea [2].
authors.forename: Jae-Hong
authors.initials: JH
authors.lastname: Kim
authors.affiliation: 1] Department of Microbiology, Catholic University of Daegu School of Medicine, 17 Duruegongwon-Ro, Nam-Gu, Daegu 705-718, Korea [2].
authors.forename: Yong-Hak
authors.initials: YH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chung-Ang University, 84 Heukseok-Ro, Dongjak-Gu, Seoul 156-756, Korea.
authors.forename: Hong-Man
authors.initials: HM
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chung-Ang University, 84 Heukseok-Ro, Dongjak-Gu, Seoul 156-756, Korea.
authors.forename: Ho-Oak
authors.initials: HO
authors.lastname: Park
authors.affiliation: Department of Manufacturing Pharmacy, Pusan National University, 63 Busandaehak-Ro, Kumjeong-Gu, Busan 609-735, Korea.
authors.forename: Nam-Chul
authors.initials: NC
authors.lastname: Ha
authors.affiliation: Department of Pathology, CHA University, 59 Yatap-Ro, Bundang-Gu, Seongnam 463-836, Korea.
authors.forename: Tae Heon
authors.initials: TH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chung-Ang University, 84 Heukseok-Ro, Dongjak-Gu, Seoul 156-756, Korea.
authors.forename: Mira
authors.initials: M
authors.lastname: Park
authors.affiliation: Department of Life Science, Chung-Ang University, 84 Heukseok-Ro, Dongjak-Gu, Seoul 156-756, Korea.
authors.forename: Kangseok
authors.initials: K
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chung-Ang University, 84 Heukseok-Ro, Dongjak-Gu, Seoul 156-756, Korea.
authors.forename: Jeehyeon
authors.initials: J
authors.lastname: Bae
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000818:Animals; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006106:Granulosa Cell Tumor / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000235:genetics*; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D012694:Serine / Q000378:metabolism; D058207:Sumoylation / Q000235:genetics; D014407:Tumor Cells, Cultured; D054875:Ubiquitination / Q000235:genetics
chemical_list: C421604:FOXL2 protein, human; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; D012694:Serine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3