Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies Journal Article
| Authors: | Veeriah, S.; Taylor, B. S.; Meng, S.; Fang, F.; Yilmaz, E.; Vivanco, I.; Janakiraman, M.; Schultz, N.; Hanrahan, A. J.; Pao, W.; Ladanyi, M.; Sander, C.; Heguy, A.; Holland, E. C.; Paty, P. B.; Mischel, P. S.; Liau, L.; Cloughesy, T. F.; Mellinghoff, I. K.; Solit, D. B.; Chan, T. A. |
| Article Title: | Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies |
| Abstract: | Mutation of the gene PARK2, which encodes an E3 ubiquitin ligase, is the most common cause of early-onset Parkinson's disease. In a search for multisite tumor suppressors, we identified PARK2 as a frequently targeted gene on chromosome 6q25.2-q27 in cancer. Here we describe inactivating somatic mutations and frequent intragenic deletions of PARK2 in human malignancies. The PARK2 mutations in cancer occur in the same domains, and sometimes at the same residues, as the germline mutations causing familial Parkinson's disease. Cancer-specific mutations abrogate the growth-suppressive effects of the PARK2 protein. PARK2 mutations in cancer decrease PARK2's E3 ligase activity, compromising its ability to ubiquitinate cyclin E and resulting in mitotic instability. These data strongly point to PARK2 as a tumor suppressor on 6q25.2-q27. Thus, PARK2, a gene that causes neuronal dysfunction when mutated in the germline, may instead contribute to oncogenesis when altered in non-neuronal somatic cells. © 2010 Nature America, Inc. All rights reserved. |
| Keywords: | controlled study; unclassified drug; somatic mutation; gene deletion; mutation; neoplasm; animals; mice; lung neoplasms; protein; colonic neoplasms; genetic association; genotype; gene frequency; genetic variation; mice, scid; cell line, tumor; carcinogenesis; tumor suppressor gene; blotting, western; ubiquitination; glioblastoma; neoplasms, experimental; transplantation, heterologous; base sequence; mitosis rate; models, molecular; protein structure, tertiary; dna mutational analysis; gene dosage; parkinson disease; ubiquitin protein ligase e3; comparative genomic hybridization; ubiquitin-protein ligases; chromosome 6q; cyclin e; park2 protein |
| Journal Title: | Nature Genetics |
| Volume: | 42 |
| Issue: | 1 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2010-01-01 |
| Start Page: | 77 |
| End Page: | 82 |
| Language: | English |
| DOI: | 10.1038/ng.491 |
| PUBMED: | 19946270 |
| PROVIDER: | scopus |
| PMCID: | PMC4002225 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 12" - "Export Date: 20 April 2011" - "CODEN: NGENE" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work