title: Parkin pathway activation mitigates glioma cell proliferation and predicts patient survival.
abstract: Mutations in the parkin gene, which encodes a ubiquitin ligase, are a major genetic cause of parkinsonism. Interestingly, parkin also plays a role in cancer as a putative tumor suppressor, and the gene is frequently targeted by deletion and inactivation in human malignant tumors. Here, we investigated a potential tumor suppressor role for parkin in gliomas. We found that parkin expression was dramatically reduced in glioma cells. Restoration of parkin expression promoted G(1) phase cell-cycle arrest and mitigated the proliferation rate of glioma cells in vitro and in vivo. Notably, parkin-expressing glioma cells showed a reduction in levels of cyclin D1, but not cyclin E, and a selective downregulation of Akt serine-473 phosphorylation and VEGF receptor levels. In accordance, cells derived from a parkin-null mouse model exhibited increased levels of cyclin D1, VEGF receptor, and Akt phosphorylation, and divided significantly faster when compared with wild-type cells, with suppression of these changes following parkin reintroduction. Clinically, analysis of parkin pathway activation was predictive for the survival outcome of patients with glioma. Taken together, our study provides mechanistic insight into the tumor suppressor function of parkin in brain tumors and suggests that measurement of parkin pathway activation may be used clinically as a prognostic tool in patients with brain tumor.
authors.affiliation: Department of Physiology, National University of Singapore, Singapore.
authors.forename: Calvin W S
authors.initials: CW
authors.lastname: Yeo
authors.forename: Felicia S L
authors.initials: FS
authors.lastname: Ng
authors.forename: Chou
authors.initials: C
authors.lastname: Chai
authors.forename: Jeanne M M
authors.initials: JM
authors.lastname: Tan
authors.forename: Geraldene R H
authors.initials: GR
authors.lastname: Koh
authors.forename: Yuk Kien
authors.initials: YK
authors.lastname: Chong
authors.forename: Lynnette W H
authors.initials: LW
authors.lastname: Koh
authors.forename: Charlene S F
authors.initials: CS
authors.lastname: Foong
authors.forename: Edwin
authors.initials: E
authors.lastname: Sandanaraj
authors.forename: Joanna D
authors.initials: JD
authors.lastname: Holbrook
authors.forename: Beng-Ti
authors.initials: BT
authors.lastname: Ang
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.forename: Carol
authors.initials: C
authors.lastname: Tang
authors.forename: Kah-Leong
authors.initials: KL
authors.lastname: Lim
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D015536:Down-Regulation; D016147:Genes, Tumor Suppressor; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011379:Prognosis; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D019938:Cyclin D1; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D040301:Vascular Endothelial Growth Factor Receptor-2