The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene.
Identifieur interne : 001557 ( Main/Exploration ); précédent : 001556; suivant : 001558The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene.
Auteurs : Léon C L. Van Kempen [Canada] ; Margaret Redpath [Canada] ; Mounib Elchebly [Canada] ; Kathleen Oros Klein [Canada] ; Andreas I. Papadakis [Canada] ; James S. Wilmott [Australie] ; Richard A. Scolyer [Australie] ; Per-Henrik Edqvist [Suède] ; Fredrik Pontén [Suède] ; Dirk Schadendorf [Allemagne] ; Anke F. Van Rijk [Canada] ; Stefan Michiels [France] ; Anne Dumay [France] ; Anne Helbling-Leclerc [France] ; Philippe Dessen [France] ; Jasper Wouters [Belgique] ; Marguerite Stass [Belgique] ; Celia M T. Greenwood [Canada] ; Ghanem E. Ghanem [Belgique] ; Joost Van Den Oord [Belgique] ; Jean Feunteun [France] ; Alan Spatz [Canada]Source :
- Science translational medicine [ 1946-6242 ] ; 2016.
Abstract
Male gender is independently and significantly associated with poor prognosis in melanoma of all clinical stages. The biological underpinnings of this sex difference remain largely unknown, but we hypothesized that gene expression from gonosomes (sex chromosomes) might play an important role. We demonstrate that loss of the inactivated X chromosome in melanomas arising in females is strongly associated with poor distant metastasis-free survival, suggesting a dosage benefit from two X chromosomes. The gonosomal protein phosphatase 2 regulatory subunit B, beta (PPP2R3B) gene is located on the pseudoautosomal region (PAR) of the X chromosome in females and the Y chromosome in males. We observed that, despite its location on the PAR that predicts equal dosage across genders, PPP2R3B expression was lower in males than in females and was independently correlated with poor clinical outcome. PPP2R3B codes for the PR70 protein, a regulatory substrate-recognizing subunit of protein phosphatase 2A. PR70 decreased melanoma growth by negatively interfering with DNA replication and cell cycle progression through its role in stabilizing the cell division cycle 6 (CDC6)-chromatin licensing and DNA replication factor 1 (CDT1) interaction, which delays the firing of origins of DNA replication. Hence, PR70 functionally behaves as an X-linked tumor suppressor gene.
DOI: 10.1126/scitranslmed.aai9188
PubMed: 27974665
Affiliations:
- Allemagne, Australie, Belgique, Canada, France, Suède
- East Middle Sweden, Nouvelle-Galles du Sud, Québec, Région de Bruxelles-Capitale, Svealand, Île-de-France
- Bruxelles, Montréal, Orsay, Paris, Sydney, Uppsala
- Université McGill, Université Paris-Sud, Université d'Uppsala, Université de Sydney, Université libre de Bruxelles
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Van Kempen</name><affiliation wicri:level="4"><nlm:affiliation>Department of Pathology, McGill University, Montreal, Quebec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pathology, McGill University, Montreal, Quebec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Redpath, Margaret" sort="Redpath, Margaret" uniqKey="Redpath M" first="Margaret" last="Redpath">Margaret Redpath</name><affiliation wicri:level="4"><nlm:affiliation>Department of Pathology, McGill University, Montreal, Quebec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pathology, McGill University, Montreal, Quebec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Elchebly, Mounib" sort="Elchebly, Mounib" uniqKey="Elchebly M" first="Mounib" last="Elchebly">Mounib Elchebly</name><affiliation wicri:level="1"><nlm:affiliation>Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Lady Davis Institute for Medical Research, Montreal, Quebec</wicri:regionArea><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Klein, Kathleen Oros" sort="Klein, Kathleen Oros" uniqKey="Klein K" first="Kathleen Oros" last="Klein">Kathleen Oros Klein</name><affiliation wicri:level="1"><nlm:affiliation>Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Lady Davis Institute for Medical Research, Montreal, Quebec</wicri:regionArea><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Papadakis, Andreas I" sort="Papadakis, Andreas I" uniqKey="Papadakis A" first="Andreas I" last="Papadakis">Andreas I. Papadakis</name><affiliation wicri:level="4"><nlm:affiliation>Department of Pathology, McGill University, Montreal, Quebec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pathology, McGill University, Montreal, Quebec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Wilmott, James S" sort="Wilmott, James S" uniqKey="Wilmott J" first="James S" last="Wilmott">James S. Wilmott</name><affiliation wicri:level="4"><nlm:affiliation>Melanoma Institute Australia, Royal Prince Alfred Hospital, and University of Sydney, Sydney, New South Wales, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Melanoma Institute Australia, Royal Prince Alfred Hospital, and University of Sydney, Sydney, New South Wales</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Scolyer, Richard A" sort="Scolyer, Richard A" uniqKey="Scolyer R" first="Richard A" last="Scolyer">Richard A. Scolyer</name><affiliation wicri:level="4"><nlm:affiliation>Melanoma Institute Australia, Royal Prince Alfred Hospital, and University of Sydney, Sydney, New South Wales, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Melanoma Institute Australia, Royal Prince Alfred Hospital, and University of Sydney, Sydney, New South Wales</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Edqvist, Per Henrik" sort="Edqvist, Per Henrik" uniqKey="Edqvist P" first="Per-Henrik" last="Edqvist">Per-Henrik Edqvist</name><affiliation wicri:level="4"><nlm:affiliation>Department of Immunology, Genetics and Pathology, and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Immunology, Genetics and Pathology, and Science for Life Laboratory, Uppsala University, Uppsala</wicri:regionArea><orgName type="university">Université d'Uppsala</orgName><placeName><settlement type="city">Uppsala</settlement><region nuts="1">Svealand</region><region nuts="1">East Middle Sweden</region></placeName></affiliation></author><author><name sortKey="Ponten, Fredrik" sort="Ponten, Fredrik" uniqKey="Ponten F" first="Fredrik" last="Pontén">Fredrik Pontén</name><affiliation wicri:level="4"><nlm:affiliation>Department of Immunology, Genetics and Pathology, and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Immunology, Genetics and Pathology, and Science for Life Laboratory, Uppsala University, Uppsala</wicri:regionArea><orgName type="university">Université d'Uppsala</orgName><placeName><settlement type="city">Uppsala</settlement><region nuts="1">Svealand</region><region nuts="1">East Middle Sweden</region></placeName></affiliation></author><author><name sortKey="Schadendorf, Dirk" sort="Schadendorf, Dirk" uniqKey="Schadendorf D" first="Dirk" last="Schadendorf">Dirk Schadendorf</name><affiliation wicri:level="1"><nlm:affiliation>Department of Dermatology, University Hospital Essen, Essen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Dermatology, University Hospital Essen, Essen</wicri:regionArea><wicri:noRegion>Essen</wicri:noRegion><wicri:noRegion>Essen</wicri:noRegion><wicri:noRegion>Essen</wicri:noRegion></affiliation></author><author><name sortKey="Van Rijk, Anke F" sort="Van Rijk, Anke F" uniqKey="Van Rijk A" first="Anke F" last="Van Rijk">Anke F. Van Rijk</name><affiliation wicri:level="1"><nlm:affiliation>Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Lady Davis Institute for Medical Research, Montreal, Quebec</wicri:regionArea><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Michiels, Stefan" sort="Michiels, Stefan" uniqKey="Michiels S" first="Stefan" last="Michiels">Stefan Michiels</name><affiliation wicri:level="1"><nlm:affiliation>Service de Biostatistique et d'Epidémiologie, Gustave Roussy, Villejuif, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Service de Biostatistique et d'Epidémiologie, Gustave Roussy, Villejuif</wicri:regionArea><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>Villejuif</wicri:noRegion></affiliation></author><author><name sortKey="Dumay, Anne" sort="Dumay, Anne" uniqKey="Dumay A" first="Anne" last="Dumay">Anne Dumay</name><affiliation wicri:level="3"><nlm:affiliation>Centre de Recherche sur l'Inflammation, INSERM, UMR S 1149, Labex Inflamex, Université Paris-Diderot Sorbonne Paris-Cité, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Centre de Recherche sur l'Inflammation, INSERM, UMR S 1149, Labex Inflamex, Université Paris-Diderot Sorbonne Paris-Cité, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Helbling Leclerc, Anne" sort="Helbling Leclerc, Anne" uniqKey="Helbling Leclerc A" first="Anne" last="Helbling-Leclerc">Anne Helbling-Leclerc</name><affiliation wicri:level="4"><nlm:affiliation>CNRS, UMR 8200, Université Paris-Sud, Villejuif, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>CNRS, UMR 8200, Université Paris-Sud, Villejuif</wicri:regionArea><wicri:noRegion>Villejuif</wicri:noRegion><orgName type="university">Université Paris-Sud</orgName><placeName><settlement type="city">Orsay</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Dessen, Philippe" sort="Dessen, Philippe" uniqKey="Dessen P" first="Philippe" last="Dessen">Philippe Dessen</name><affiliation wicri:level="4"><nlm:affiliation>Hématopoïèse normale et pathologique, INSERM UMR 1170, Université Paris-Sud, Gustave Roussy, Villejuif, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Hématopoïèse normale et pathologique, INSERM UMR 1170, Université Paris-Sud, Gustave Roussy, Villejuif</wicri:regionArea><wicri:noRegion>Villejuif</wicri:noRegion><orgName type="university">Université Paris-Sud</orgName><placeName><settlement type="city">Orsay</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Wouters, Jasper" sort="Wouters, Jasper" uniqKey="Wouters J" first="Jasper" last="Wouters">Jasper Wouters</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Translational Cell and Tissue Research, KU Leuven, Leuven, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Translational Cell and Tissue Research, KU Leuven, Leuven</wicri:regionArea><wicri:noRegion>Leuven</wicri:noRegion></affiliation></author><author><name sortKey="Stass, Marguerite" sort="Stass, Marguerite" uniqKey="Stass M" first="Marguerite" last="Stass">Marguerite Stass</name><affiliation wicri:level="1"><nlm:affiliation>Department of Surgical Oncology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Surgical Oncology, University Hospitals Leuven, KU Leuven, Leuven</wicri:regionArea><wicri:noRegion>Leuven</wicri:noRegion></affiliation></author><author><name sortKey="Greenwood, Celia M T" sort="Greenwood, Celia M T" uniqKey="Greenwood C" first="Celia M T" last="Greenwood">Celia M T. Greenwood</name><affiliation wicri:level="1"><nlm:affiliation>Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Lady Davis Institute for Medical Research, Montreal, Quebec</wicri:regionArea><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Ghanem, Ghanem E" sort="Ghanem, Ghanem E" uniqKey="Ghanem G" first="Ghanem E" last="Ghanem">Ghanem E. Ghanem</name><affiliation wicri:level="4"><nlm:affiliation>Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region><settlement type="city">Bruxelles</settlement></placeName><orgName type="university">Université libre de Bruxelles</orgName></affiliation></author><author><name sortKey="Van Den Oord, Joost" sort="Van Den Oord, Joost" uniqKey="Van Den Oord J" first="Joost" last="Van Den Oord">Joost Van Den Oord</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Translational Cell and Tissue Research, KU Leuven, Leuven, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Translational Cell and Tissue Research, KU Leuven, Leuven</wicri:regionArea><wicri:noRegion>Leuven</wicri:noRegion></affiliation></author><author><name sortKey="Feunteun, Jean" sort="Feunteun, Jean" uniqKey="Feunteun J" first="Jean" last="Feunteun">Jean Feunteun</name><affiliation wicri:level="4"><nlm:affiliation>CNRS UMR 8200, Universite Paris-Sud, Gustave Roussy, Villejuif, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>CNRS UMR 8200, Universite Paris-Sud, Gustave Roussy, Villejuif</wicri:regionArea><wicri:noRegion>Villejuif</wicri:noRegion><orgName type="university">Université Paris-Sud</orgName><placeName><settlement type="city">Orsay</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Spatz, Alan" sort="Spatz, Alan" uniqKey="Spatz A" first="Alan" last="Spatz">Alan Spatz</name><affiliation wicri:level="4"><nlm:affiliation>Department of Pathology, McGill University, Montreal, Quebec, Canada. alan.spatz@mcgill.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pathology, McGill University, Montreal, Quebec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author></analytic><series><title level="j">Science translational medicine</title><idno type="eISSN">1946-6242</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">Male gender is independently and significantly associated with poor prognosis in melanoma of all clinical stages. The biological underpinnings of this sex difference remain largely unknown, but we hypothesized that gene expression from gonosomes (sex chromosomes) might play an important role. We demonstrate that loss of the inactivated X chromosome in melanomas arising in females is strongly associated with poor distant metastasis-free survival, suggesting a dosage benefit from two X chromosomes. The gonosomal protein phosphatase 2 regulatory subunit B, beta (PPP2R3B) gene is located on the pseudoautosomal region (PAR) of the X chromosome in females and the Y chromosome in males. We observed that, despite its location on the PAR that predicts equal dosage across genders, PPP2R3B expression was lower in males than in females and was independently correlated with poor clinical outcome. PPP2R3B codes for the PR70 protein, a regulatory substrate-recognizing subunit of protein phosphatase 2A. PR70 decreased melanoma growth by negatively interfering with DNA replication and cell cycle progression through its role in stabilizing the cell division cycle 6 (CDC6)-chromatin licensing and DNA replication factor 1 (CDT1) interaction, which delays the firing of origins of DNA replication. Hence, PR70 functionally behaves as an X-linked tumor suppressor gene.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Australie</li><li>Belgique</li><li>Canada</li><li>France</li><li>Suède</li></country><region><li>East Middle Sweden</li><li>Nouvelle-Galles du Sud</li><li>Québec</li><li>Région de Bruxelles-Capitale</li><li>Svealand</li><li>Île-de-France</li></region><settlement><li>Bruxelles</li><li>Montréal</li><li>Orsay</li><li>Paris</li><li>Sydney</li><li>Uppsala</li></settlement><orgName><li>Université McGill</li><li>Université Paris-Sud</li><li>Université d'Uppsala</li><li>Université de Sydney</li><li>Université libre de Bruxelles</li></orgName></list><tree><country name="Canada"><region name="Québec"><name sortKey="Van Kempen, Leon C L" sort="Van Kempen, Leon C L" uniqKey="Van Kempen L" first="Léon C L" last="Van Kempen">Léon C L. Van Kempen</name></region><name sortKey="Elchebly, Mounib" sort="Elchebly, Mounib" uniqKey="Elchebly M" first="Mounib" last="Elchebly">Mounib Elchebly</name><name sortKey="Greenwood, Celia M T" sort="Greenwood, Celia M T" uniqKey="Greenwood C" first="Celia M T" last="Greenwood">Celia M T. Greenwood</name><name sortKey="Klein, Kathleen Oros" sort="Klein, Kathleen Oros" uniqKey="Klein K" first="Kathleen Oros" last="Klein">Kathleen Oros Klein</name><name sortKey="Papadakis, Andreas I" sort="Papadakis, Andreas I" uniqKey="Papadakis A" first="Andreas I" last="Papadakis">Andreas I. Papadakis</name><name sortKey="Redpath, Margaret" sort="Redpath, Margaret" uniqKey="Redpath M" first="Margaret" last="Redpath">Margaret Redpath</name><name sortKey="Spatz, Alan" sort="Spatz, Alan" uniqKey="Spatz A" first="Alan" last="Spatz">Alan Spatz</name><name sortKey="Van Rijk, Anke F" sort="Van Rijk, Anke F" uniqKey="Van Rijk A" first="Anke F" last="Van Rijk">Anke F. Van Rijk</name></country><country name="Australie"><region name="Nouvelle-Galles du Sud"><name sortKey="Wilmott, James S" sort="Wilmott, James S" uniqKey="Wilmott J" first="James S" last="Wilmott">James S. Wilmott</name></region><name sortKey="Scolyer, Richard A" sort="Scolyer, Richard A" uniqKey="Scolyer R" first="Richard A" last="Scolyer">Richard A. Scolyer</name></country><country name="Suède"><region name="Svealand"><name sortKey="Edqvist, Per Henrik" sort="Edqvist, Per Henrik" uniqKey="Edqvist P" first="Per-Henrik" last="Edqvist">Per-Henrik Edqvist</name></region><name sortKey="Ponten, Fredrik" sort="Ponten, Fredrik" uniqKey="Ponten F" first="Fredrik" last="Pontén">Fredrik Pontén</name></country><country name="Allemagne"><noRegion><name sortKey="Schadendorf, Dirk" sort="Schadendorf, Dirk" uniqKey="Schadendorf D" first="Dirk" last="Schadendorf">Dirk Schadendorf</name></noRegion></country><country name="France"><noRegion><name sortKey="Michiels, Stefan" sort="Michiels, Stefan" uniqKey="Michiels S" first="Stefan" last="Michiels">Stefan Michiels</name></noRegion><name sortKey="Dessen, Philippe" sort="Dessen, Philippe" uniqKey="Dessen P" first="Philippe" last="Dessen">Philippe Dessen</name><name sortKey="Dumay, Anne" sort="Dumay, Anne" uniqKey="Dumay A" first="Anne" last="Dumay">Anne Dumay</name><name sortKey="Feunteun, Jean" sort="Feunteun, Jean" uniqKey="Feunteun J" first="Jean" last="Feunteun">Jean Feunteun</name><name sortKey="Helbling Leclerc, Anne" sort="Helbling Leclerc, Anne" uniqKey="Helbling Leclerc A" first="Anne" last="Helbling-Leclerc">Anne Helbling-Leclerc</name></country><country name="Belgique"><noRegion><name sortKey="Wouters, Jasper" sort="Wouters, Jasper" uniqKey="Wouters J" first="Jasper" last="Wouters">Jasper Wouters</name></noRegion><name sortKey="Ghanem, Ghanem E" sort="Ghanem, Ghanem E" uniqKey="Ghanem G" first="Ghanem E" last="Ghanem">Ghanem E. Ghanem</name><name sortKey="Stass, Marguerite" sort="Stass, Marguerite" uniqKey="Stass M" first="Marguerite" last="Stass">Marguerite Stass</name><name sortKey="Van Den Oord, Joost" sort="Van Den Oord, Joost" uniqKey="Van Den Oord J" first="Joost" last="Van Den Oord">Joost Van Den Oord</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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