Veeriah, S. et al. Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies. Nature Genet. 42, 77-82

Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Nature Genetics (Impact Factor: 29.35). 11/2009; 42(1):77-82. DOI: 10.1038/ng.491
Source: PubMed


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.

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    • "X-axis represent the size of the aberrations in Mb, y-axis represents the frequency in the data sets. Grey bars under the plots indicate the size range of somatic focal CNAs and CNVs. in the vicinity of common fragile sites (CFS) genes such as FHIT, WWOX and PARK2 [32] [52]. CNAs serve as important predictive and/or prognostic biomarkers in the clinic. "
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    ABSTRACT: The extent of focal chromosomal copy number aberrations (CNAs) in cancer has been uncovered through technical innovations and this discovery has been critical for the identification of new cancer driver genes in genomics projects such as TCGA and ICGC. Unlike constitutive copy number variations (CNVs), focal CNAs are the result of many selection events during the evolution of cancer genomes. Therefore it is possible that a single gene in a focal CNA gives the tumor a selective growth advantage. This concept has been instrumental in the discovery of new cancer driver genes. However, focal CNAs lack a consensus definition, therefore we propose one based on pragmatic considerations. We also describe different strategies to identify focal CNAs and procedures to distinguish them from large CNAs and CNVs.
    Full-text · Article · Aug 2014 · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
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    • "PARK2 mutations also explain ~15% of the sporadic cases with onset before 45 [1, 2] and act as susceptibility alleles for late-onset forms of Parkinson disease (2% of cases) [3]. Along with Parkinsonism forms, PARK2 gene has been linked to other human pathologies, such as Alzheimer disease [4], autism [5], multiple sclerosis [6], cancer [7, 8], leprosy [9], type 2 diabetes mellitus [10], and myositis [11]. "
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    ABSTRACT: Parkinson protein 2, E3 ubiquitin protein ligase ( PARK2 ) gene mutations are the most frequent causes of autosomal recessive early onset Parkinson’s disease and juvenile Parkinson disease. Parkin deficiency has also been linked to other human pathologies, for example, sporadic Parkinson disease, Alzheimer disease, autism, and cancer. PARK2 primary transcript undergoes an extensive alternative splicing, which enhances transcriptomic diversification. To date several PARK2 splice variants have been identified; however, the expression and distribution of parkin isoforms have not been deeply investigated yet. Here, the currently known PARK2 gene transcripts and relative predicted encoded proteins in human, rat, and mouse are reviewed. By analyzing the literature, we highlight the existing data showing the presence of multiple parkin isoforms in the brain. Their expression emerges from conflicting results regarding the electrophoretic mobility of the protein, but it is also assumed from discrepant observations on the cellular and tissue distribution of parkin. Although the characterization of each predicted isoforms is complex, since they often diverge only for few amino acids, analysis of their expression patterns in the brain might account for the different pathogenetic effects linked to PARK2 gene mutations.
    Full-text · Article · Jul 2014 · BioMed Research International
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    • "Mutations in PARK2 gene are responsible for the development of a form of autosomal recessive juvenile Parkinsonism (AR-JP) characterized by all the classical symptoms of Parkinson disease (PD), such as tremor, rigidity and bradykinesia [2]. In addition to AR-JP, PARK2 has been recently linked to cancer [3] [4], leprosy [5], autism [6], type 2 diabetes mellitus [7] and Alzheimer's disease [8]. PARK2 gene spans more than 1.38 Mb of genomic DNA in the long arm of chromosome 6 (6q25.2-q27) "
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    ABSTRACT: The completion of the Human Genome Project aroused renewed interest in alternative splicing, an efficient and widespread mechanism that generates multiple protein isoforms from individual genes. Although our knowledge about alternative splicing is growing exponentially, its real impact on cellular life is still to be clarified. Connecting all splicing features (genes, splice transcripts, isoforms, and relative functions) may be useful to resolve this tangle. Herein, we will start from the case of a single gene, Parkinson protein 2, E3 ubiquitin protein ligase (PARK2), one of the largest in our genome. This gene is implicated in the pathogenesis of autosomal recessive juvenile Parkinsonism and it has been recently linked to cancer, leprosy, autism, type 2 diabetes mellitus and Alzheimer's disease. PARK2 primary transcript undergoes an extensive alternative splicing, which enhances transcriptomic diversification and protein diversity in tissues and cells. This review will provide an update of all human PARK2 alternative splice transcripts and isoforms presently known, and correlate them to those in rat and mouse, two common animal models for studying human disease genes. Alternative splicing relies upon a complex process that could be easily altered by both cis and trans-acting mutations. Although the contribution of PARK2 splicing in human disease remains to be fully explored, some evidences show disruption of this versatile form of genetic regulation may have pathological consequences.
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