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Agilent 244K aCGH data for colon cancer samples

ABSTRACT: Mutation of the gene PARK2 is the most common cause of early-onset Parkinson's Disease (PD)1,2. PARK2 encodes a gene product with E3 ubiquitin ligase activity3. 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 PD. Cancer-specific mutations abrogate the growth suppressive effects of PARK2. PARK2 mutations in cancer decrease the gene product'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. PARK2, a gene that causes neuronal dysfunction when mutated in the germline, may instead contribute to oncogenesis when altered in non-neuronal somatic cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE18638 | GEO | 2009/10/21

SECONDARY ACCESSION(S): PRJNA121415

REPOSITORIES: GEO

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Project description:Mutations in PARK2 gene are the most frequent cause of familial forms of Parkinson’s disease (PD). This gene encodes Parkin, an E3 ubiquitin ligase involved in several cellular mechanisms, such as the mitophagic process. Mutations in this gene, which cause the loss of function of Parkin, are responsible for the accumulation of damaged mitochondria. This improper disposal may generate increased levels of ROS, lower ATP production and apoptosis activation. Given the importance of mitochondrial dysfunctions and mitophagy impairment in PD pathogenesis, the aim of the present project was to investigate both whole-cell and mitochondrial proteome alterations in human skin fibroblasts of PARK2-mutated patients. To this purpose, total and mitochondrial-enriched protein fractions from fibroblasts of five PARK2-mutated patients and five control subjects were analyzed by quantitative shotgun proteomics, in order to identify proteins specifically altered by Parkin loss. Both the network-based and the GSEA analysis of proteomics results pointed out the importance of pathways in which Rab GTPase proteins are involved. An alteration of their levels also in the mitochondrial fraction may indicate a re-localization of these GTP/GDP molecular switches, master regulators of membrane trafficking. To have a more comprehensive view of the mitochondrial alterations due to PARK2 mutations, we investigated the impact of Parkin loss on mitochondrial function and network morphology. We unveiled that the mitochondrial membrane potential was reduced in PARK2-mutated patients. Nevertheless, PINK1 did not accumulate on depolarized mitochondria. Even after the treatment with CCCP, an ionophore that triggers mitophagy, the accumulation of PINK1 was less efficient in PARK2-mutated patients than in controls derived fibroblasts. The analysis of the mitochondrial network morphology showed a filamentous network with mitochondria distributed all over the cell that was comparable between PARK2-mutated patients and control subjects. Thus, our results suggested that the network morphology was not influenced by the mitochondrial depolarization and by the lack of Parkin, revealing a possible impairment of fission and, more in general, of mitochondrial dynamics. In conclusion, the present work highlighted new molecular factors and pathways altered by PARK2 mutations. Furthermore, we obtained a definition of the mitochondrial landscape and molecular mechanisms underlying the PARK2 form of Parkinson’s disease, which will help to unravel possible biochemical pathways altered also in the sporadic form of the disease. Indeed, it is known that in sporadic cases the genetic/epigenetic background and the environment lead over time to mitochondria impairment and to the accumulation of damaged organelles.

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Agilent 244K aCGH data for colon cancer samples

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