Parkin Somatic Mutations Link Melanoma and Parkinson's Disease.
Identifieur interne : 000029 ( France/Analysis ); précédent : 000028; suivant : 000030Parkin Somatic Mutations Link Melanoma and Parkinson's Disease.
Auteurs : Lotan Levin [Israël] ; Shani Srour [Israël] ; Jared Gartner [États-Unis] ; Oxana Kapitansky [Israël] ; Nouar Qutob [Israël] ; Shani Dror [Israël] ; Tamar Golan [Israël] ; Roy Dayan [Israël] ; Ronen Brener [Israël] ; Tamar Ziv [Israël] ; Mehdi Khaled [France] ; Ora Schueler-Furman [Israël] ; Yardena Samuels [Israël] ; Carmit Levy [Israël]Source :
- Journal of genetics and genomics = Yi chuan xue bao [ 1673-8527 ] ; 2016.
Abstract
Epidemiological studies suggest a direct link between melanoma and Parkinson's disease (PD); however, the underlying molecular basis is unknown. Since mutations in Parkin are the major driver of early-onset PD and Parkin was recently reported to play a role in cancer development, we hypothesized that Parkin links melanoma and PD. By analyzing whole exome/genome sequencing of Parkin from 246 melanoma patients, we identified five non-synonymous mutations, three synonymous mutations, and one splice region variant in Parkin in 3.6% of the samples. In vitro analysis showed that wild-type Parkin plays a tumor suppressive role in melanoma development resulting in cell-cycle arrest, reduction of metabolic activity, and apoptosis. Using a mass spectrometry-based analysis, we identified potential Parkin substrates in melanoma and generated a functional protein association network. The activity of mutated Parkin was assessed by protein structure modeling and examination of Parkin E3 ligase activity. The Parkin-E28K mutation impairs Parkin ubiquitination activity and abolishes its tumor suppressive effect. Taken together, our analysis of genomic sequence and in vitro data indicate that Parkin is a potential link between melanoma and Parkinson's disease. Our findings suggest new approaches for early diagnosis and treatment against both diseases.
DOI: 10.1016/j.jgg.2016.05.005
PubMed: 27297116
Affiliations:
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Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.</nlm:affiliation><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100</wicri:regionArea><wicri:noRegion>Rehovot 76100</wicri:noRegion></affiliation></author><author><name sortKey="Dror, Shani" sort="Dror, Shani" uniqKey="Dror S" first="Shani" last="Dror">Shani Dror</name><affiliation wicri:level="1"><nlm:affiliation>Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.</nlm:affiliation><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978</wicri:regionArea><wicri:noRegion>Tel Aviv 69978</wicri:noRegion></affiliation></author><author><name sortKey="Golan, Tamar" sort="Golan, Tamar" uniqKey="Golan T" first="Tamar" last="Golan">Tamar Golan</name><affiliation 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sortKey="Brener, Ronen" sort="Brener, Ronen" uniqKey="Brener R" first="Ronen" last="Brener">Ronen Brener</name><affiliation wicri:level="1"><nlm:affiliation>Oncology Institute, Edith Wolfson Medical Center, Holon 5822012, Israel.</nlm:affiliation><country xml:lang="fr">Israël</country><wicri:regionArea>Oncology Institute, Edith Wolfson Medical Center, Holon 5822012</wicri:regionArea><wicri:noRegion>Holon 5822012</wicri:noRegion></affiliation></author><author><name sortKey="Ziv, Tamar" sort="Ziv, Tamar" uniqKey="Ziv T" first="Tamar" last="Ziv">Tamar Ziv</name><affiliation wicri:level="1"><nlm:affiliation>Technion Smoler Proteomics Center, Faculty of Biology, Technion - Israel Institute of Technology, Haifa 32000, Israel.</nlm:affiliation><country xml:lang="fr">Israël</country><wicri:regionArea>Technion Smoler Proteomics Center, Faculty of Biology, Technion - Israel Institute of Technology, Haifa 32000</wicri:regionArea><wicri:noRegion>Haifa 32000</wicri:noRegion></affiliation></author><author><name sortKey="Khaled, Mehdi" sort="Khaled, Mehdi" uniqKey="Khaled M" first="Mehdi" last="Khaled">Mehdi Khaled</name><affiliation wicri:level="1"><nlm:affiliation>Institut Gustave Roussy, INSERM U753, Villejuif 94805, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut Gustave Roussy, INSERM U753, Villejuif 94805</wicri:regionArea><wicri:noRegion>94805</wicri:noRegion><wicri:noRegion>94805</wicri:noRegion></affiliation></author><author><name sortKey="Schueler Furman, Ora" sort="Schueler Furman, Ora" uniqKey="Schueler Furman O" first="Ora" last="Schueler-Furman">Ora Schueler-Furman</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University, Jerusalem 91120, Israel.</nlm:affiliation><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University, Jerusalem 91120</wicri:regionArea><wicri:noRegion>Jerusalem 91120</wicri:noRegion></affiliation></author><author><name sortKey="Samuels, Yardena" sort="Samuels, Yardena" uniqKey="Samuels Y" first="Yardena" last="Samuels">Yardena Samuels</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.</nlm:affiliation><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100</wicri:regionArea><wicri:noRegion>Rehovot 76100</wicri:noRegion></affiliation></author><author><name sortKey="Levy, Carmit" sort="Levy, Carmit" uniqKey="Levy C" first="Carmit" last="Levy">Carmit Levy</name><affiliation wicri:level="1"><nlm:affiliation>Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: carmitlevy@post.tau.ac.il.</nlm:affiliation><country xml:lang="fr">Israël</country><wicri:regionArea>Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978</wicri:regionArea><wicri:noRegion>Tel Aviv 69978</wicri:noRegion></affiliation></author></analytic><series><title level="j">Journal of genetics and genomics = Yi chuan xue bao</title><idno type="ISSN">1673-8527</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Epidemiological studies suggest a direct link between melanoma and Parkinson's disease (PD); however, the underlying molecular basis is unknown. Since mutations in Parkin are the major driver of early-onset PD and Parkin was recently reported to play a role in cancer development, we hypothesized that Parkin links melanoma and PD. By analyzing whole exome/genome sequencing of Parkin from 246 melanoma patients, we identified five non-synonymous mutations, three synonymous mutations, and one splice region variant in Parkin in 3.6% of the samples. In vitro analysis showed that wild-type Parkin plays a tumor suppressive role in melanoma development resulting in cell-cycle arrest, reduction of metabolic activity, and apoptosis. Using a mass spectrometry-based analysis, we identified potential Parkin substrates in melanoma and generated a functional protein association network. The activity of mutated Parkin was assessed by protein structure modeling and examination of Parkin E3 ligase activity. The Parkin-E28K mutation impairs Parkin ubiquitination activity and abolishes its tumor suppressive effect. Taken together, our analysis of genomic sequence and in vitro data indicate that Parkin is a potential link between melanoma and Parkinson's disease. Our findings suggest new approaches for early diagnosis and treatment against both diseases.</div></front></TEI><affiliations><list><country><li>France</li><li>Israël</li><li>États-Unis</li></country><region><li>Maryland</li></region></list><tree><country name="Israël"><noRegion><name sortKey="Levin, Lotan" sort="Levin, Lotan" uniqKey="Levin L" first="Lotan" last="Levin">Lotan Levin</name></noRegion><name sortKey="Brener, Ronen" sort="Brener, Ronen" uniqKey="Brener R" first="Ronen" last="Brener">Ronen Brener</name><name sortKey="Dayan, Roy" sort="Dayan, Roy" uniqKey="Dayan R" first="Roy" last="Dayan">Roy Dayan</name><name sortKey="Dror, Shani" sort="Dror, Shani" uniqKey="Dror S" first="Shani" last="Dror">Shani Dror</name><name sortKey="Golan, Tamar" sort="Golan, Tamar" uniqKey="Golan T" first="Tamar" last="Golan">Tamar Golan</name><name sortKey="Kapitansky, Oxana" sort="Kapitansky, Oxana" uniqKey="Kapitansky O" first="Oxana" last="Kapitansky">Oxana Kapitansky</name><name sortKey="Levy, Carmit" sort="Levy, Carmit" uniqKey="Levy C" first="Carmit" last="Levy">Carmit Levy</name><name sortKey="Qutob, Nouar" sort="Qutob, Nouar" uniqKey="Qutob N" first="Nouar" last="Qutob">Nouar Qutob</name><name sortKey="Samuels, Yardena" sort="Samuels, Yardena" uniqKey="Samuels Y" first="Yardena" last="Samuels">Yardena Samuels</name><name sortKey="Schueler Furman, Ora" sort="Schueler Furman, Ora" uniqKey="Schueler Furman O" first="Ora" last="Schueler-Furman">Ora Schueler-Furman</name><name sortKey="Srour, Shani" sort="Srour, Shani" uniqKey="Srour S" first="Shani" last="Srour">Shani Srour</name><name sortKey="Ziv, Tamar" sort="Ziv, Tamar" uniqKey="Ziv T" first="Tamar" last="Ziv">Tamar Ziv</name></country><country name="États-Unis"><region name="Maryland"><name sortKey="Gartner, Jared" sort="Gartner, Jared" uniqKey="Gartner J" first="Jared" last="Gartner">Jared Gartner</name></region></country><country name="France"><noRegion><name sortKey="Khaled, Mehdi" sort="Khaled, Mehdi" uniqKey="Khaled M" first="Mehdi" last="Khaled">Mehdi Khaled</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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