title: Pan-Cancer Analysis Links PARK2 to BCL-XL-Dependent Control of Apoptosis.
abstract: Mutation of the PARK2 gene can promote both Parkinson's Disease and cancer, yet the underlying mechanisms of how PARK2 controls cellular physiology is incompletely understood. Here, we show that the PARK2 tumor suppressor controls the apoptotic regulator BCL-XL and modulates programmed cell death. Analysis of approximately 10,000 tumor genomes uncovers a striking pattern of mutual exclusivity between PARK2 genetic loss and amplification of BCL2L1, implicating these genes in a common pathway. PARK2 directly binds to and ubiquitinates BCL-XL. Inactivation of PARK2 leads to aberrant accumulation of BCL-XL both in vitro and in vivo, and cancer-specific mutations in PARK2 abrogate the ability of the ubiquitin E3 ligase to target BCL-XL for degradation. Furthermore, PARK2 modulates mitochondrial depolarization and apoptosis in a BCL-XL-dependent manner. Thus, like genes at the nodal points of growth arrest pathways such as p53, the PARK2 tumor suppressor is able to exert its antiproliferative effects by regulating both cell cycle progression and programmed cell death.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Yongxing
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Schumacher
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Wei H
authors.initials: WH
authors.lastname: Wu
authors.affiliation: Weill Cornell College of Medicine, New York, NY, USA.
authors.forename: Fanying
authors.initials: F
authors.lastname: Tang
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Cancer Genome Characterization, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell College of Medicine, New York, NY, USA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: chant@mskcc.org.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
mesh_terms: D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D051020:bcl-X Protein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D046988:Proteasome Endopeptidase Complex