Parkin Somatic Mutations Link Melanoma and Parkinson's Disease.
Identifieur interne : 000107 ( PubMed/Checkpoint ); précédent : 000106; suivant : 000108Parkin 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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<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>
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<Abstract><AbstractText>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.</AbstractText>
<CopyrightInformation>Copyright © 2016. Published by Elsevier Ltd.</CopyrightInformation>
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<ForeName>Ronen</ForeName>
<Initials>R</Initials>
<AffiliationInfo><Affiliation>Oncology Institute, Edith Wolfson Medical Center, Holon 5822012, Israel.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ziv</LastName>
<ForeName>Tamar</ForeName>
<Initials>T</Initials>
<AffiliationInfo><Affiliation>Technion Smoler Proteomics Center, Faculty of Biology, Technion - Israel Institute of Technology, Haifa 32000, Israel.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Khaled</LastName>
<ForeName>Mehdi</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Institut Gustave Roussy, INSERM U753, Villejuif 94805, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Schueler-Furman</LastName>
<ForeName>Ora</ForeName>
<Initials>O</Initials>
<AffiliationInfo><Affiliation>Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University, Jerusalem 91120, Israel.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Samuels</LastName>
<ForeName>Yardena</ForeName>
<Initials>Y</Initials>
<AffiliationInfo><Affiliation>Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Levy</LastName>
<ForeName>Carmit</ForeName>
<Initials>C</Initials>
<AffiliationInfo><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.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2016</Year>
<Month>05</Month>
<Day>13</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>China</Country>
<MedlineTA>J Genet Genomics</MedlineTA>
<NlmUniqueID>101304616</NlmUniqueID>
<ISSNLinking>1673-8527</ISSNLinking>
</MedlineJournalInfo>
<CitationSubset>IM</CitationSubset>
<KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Melanoma</Keyword>
<Keyword MajorTopicYN="N">Mutation</Keyword>
<Keyword MajorTopicYN="N">Parkin</Keyword>
<Keyword MajorTopicYN="N">Parkinson's disease</Keyword>
</KeywordList>
</MedlineCitation>
<PubmedData><History><PubMedPubDate PubStatus="received"><Year>2015</Year>
<Month>10</Month>
<Day>30</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="revised"><Year>2016</Year>
<Month>05</Month>
<Day>11</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="accepted"><Year>2016</Year>
<Month>05</Month>
<Day>12</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="entrez"><Year>2016</Year>
<Month>6</Month>
<Day>15</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="pubmed"><Year>2016</Year>
<Month>6</Month>
<Day>15</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="medline"><Year>2016</Year>
<Month>6</Month>
<Day>15</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
</History>
<PublicationStatus>ppublish</PublicationStatus>
<ArticleIdList><ArticleId IdType="pubmed">27297116</ArticleId>
<ArticleId IdType="pii">S1673-8527(16)30056-X</ArticleId>
<ArticleId IdType="doi">10.1016/j.jgg.2016.05.005</ArticleId>
</ArticleIdList>
</PubmedData>
</pubmed>
<affiliations><list><country><li>France</li>
<li>Israël</li>
<li>États-Unis</li>
</country>
<region><li>Maryland</li>
<li>Île-de-France</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"><region name="Île-de-France"><name sortKey="Khaled, Mehdi" sort="Khaled, Mehdi" uniqKey="Khaled M" first="Mehdi" last="Khaled">Mehdi Khaled</name>
</region>
</country>
</tree>
</affiliations>
</record>
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