title: The Parkinson's gene PINK1 regulates cell cycle progression and promotes cancer-associated phenotypes.
abstract: PINK1 (phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-induced kinase 1), a Parkinson's disease-associated gene, was identified originally because of its induction by the tumor-suppressor PTEN. PINK1 promotes cell survival and potentially metastatic functions and protects against cell stressors including chemotherapeutic agents. However, the mechanisms underlying PINK1 function in cancer cell biology are unclear. Here, using several model systems, we show that PINK1 deletion significantly reduced cancer-associated phenotypes including cell proliferation, colony formation and invasiveness, which were restored by human PINK1 overexpression. Results show that PINK1 deletion causes major defects in cell cycle progression in immortalized mouse embryonic fibroblasts (MEFs) from PINK1(-/-) mice, and in BE(2)-M17 cells stably transduced with short hairpin RNA against PINK1. Detailed cell cycle analyses of MEF cell lines from several PINK1(-/-) mice demonstrate an increased proportion of cells in G2/M and decreased number of cells in G1 following release from nocodazole block. This was concomitant with increased double and multi-nucleated cells, a reduced ability to undergo cytokinesis and to re-enter G1, and significant alterations in cell cycle markers, including failure to increase cyclin D1, all indicative of mitotic arrest. PINK1(-/-) cells also demonstrated ineffective cell cycle exit following serum deprivation. Cell cycle defects associated with PINK1 deficiency occur at points critical for cell division, growth and stress resistance in cancer cells were rescued by ectopic expression of human PINK1 and demonstrated PINK1 kinase dependence. The importance of PINK1 for cell cycle control is further supported by results showing that cell cycle deficits induced by PINK1 deletion were linked mechanistically to aberrant mitochondrial fission and its regulation by dynamin-related protein-1 (Drp1), known to be critical for progression of mitosis. Our data indicate that PINK1 has tumor-promoting properties and demonstrates a new function for PINK1 as a regulator of the cell cycle.
authors.affiliation: School of Biochemistry and Cell Biology, BioSciences Institute, University College Cork, Cork, Ireland.
authors.forename: C H
authors.initials: CH
authors.lastname: O'Flanagan
authors.affiliation: 1] VIB Center for the Biology of Disease, VIB, Leuven, Belgium [2] Center for Human Genetics and LIND, KU Leuven, Leuven, Belgium.
authors.forename: V A
authors.initials: VA
authors.lastname: Morais
authors.affiliation: 1] Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Developmental Genetics, München-Neuherberg, Germany [2] Technische Universität München-Weihenstephan, Lehrstuhl für Entwicklungsgenetik, c/o Helmholtz Zentrum München, München-Neuherberg, Germany [3] German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Wurst
authors.affiliation: 1] VIB Center for the Biology of Disease, VIB, Leuven, Belgium [2] Center for Human Genetics and LIND, KU Leuven, Leuven, Belgium [3] UCL Institute of Neurology, London, UK.
authors.forename: B
authors.initials: B
authors.lastname: De Strooper
authors.affiliation: School of Biochemistry and Cell Biology, BioSciences Institute, University College Cork, Cork, Ireland.
authors.forename: C
authors.initials: C
authors.lastname: O'Neill
mesh_terms: D000818:Animals; D002455:Cell Division / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000235:genetics; D019938:Cyclin D1 / Q000096:biosynthesis; D048749:Cytokinesis / Q000235:genetics; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics*; D061986:MCF-7 Cells; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D000099202:PTEN-Induced Putative Kinase
chemical_list: D019938:Cyclin D1; D034281:Dynamins; D020558:GTP Phosphohydrolases; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D011494:Protein Kinases; D034741:RNA, Small Interfering; D000099202:PTEN-Induced Putative Kinase; C530104:CCND1 protein, human; C110768:DNM1L protein, human