Publication

The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene

van Kempen, L. C. L., Redpath, M., Elchebly, M., Klein, K. O., Papadakis, A. I., Wilmott, J. S., Scolyer, R. A., Edqvist, P-H., Pontén, F., Schadendorf, D., van Rijk, A. F., Michiels, S., Dumay, A., Helbling-Leclerc, A., Dessen, P., Wouters, J., Stass, M., Greenwood, C. M. T., Ghanem, G. E., van den Oord, J., Feunteun, J. & Spatz, A., 14-Dec-2016, In : Science Translational Medicine. 8, 369, 369ra177.

Research output: Contribution to journalArticleAcademicpeer-review

APA

van Kempen, L. C. L., Redpath, M., Elchebly, M., Klein, K. O., Papadakis, A. I., Wilmott, J. S., ... Spatz, A. (2016). The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene. Science Translational Medicine, 8(369), [369ra177]. https://doi.org/10.1126/scitranslmed.aai9188

Author

van Kempen, Léon C L ; Redpath, Margaret ; Elchebly, Mounib ; Klein, Kathleen Oros ; Papadakis, Andreas I ; Wilmott, James S ; Scolyer, Richard A ; Edqvist, Per-Henrik ; Pontén, Fredrik ; Schadendorf, Dirk ; van Rijk, Anke F ; Michiels, Stefan ; Dumay, Anne ; Helbling-Leclerc, Anne ; Dessen, Philippe ; Wouters, Jasper ; Stass, Marguerite ; Greenwood, Celia M T ; Ghanem, Ghanem E ; van den Oord, Joost ; Feunteun, Jean ; Spatz, Alan. / The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene. In: Science Translational Medicine. 2016 ; Vol. 8, No. 369.

Harvard

van Kempen, LCL, Redpath, M, Elchebly, M, Klein, KO, Papadakis, AI, Wilmott, JS, Scolyer, RA, Edqvist, P-H, Pontén, F, Schadendorf, D, van Rijk, AF, Michiels, S, Dumay, A, Helbling-Leclerc, A, Dessen, P, Wouters, J, Stass, M, Greenwood, CMT, Ghanem, GE, van den Oord, J, Feunteun, J & Spatz, A 2016, 'The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene' Science Translational Medicine, vol. 8, no. 369, 369ra177. https://doi.org/10.1126/scitranslmed.aai9188

Standard

The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene. / van Kempen, Léon C L; Redpath, Margaret; Elchebly, Mounib; Klein, Kathleen Oros; Papadakis, Andreas I; Wilmott, James S; Scolyer, Richard A; Edqvist, Per-Henrik; Pontén, Fredrik; Schadendorf, Dirk; van Rijk, Anke F; Michiels, Stefan; Dumay, Anne; Helbling-Leclerc, Anne; Dessen, Philippe; Wouters, Jasper; Stass, Marguerite; Greenwood, Celia M T; Ghanem, Ghanem E; van den Oord, Joost; Feunteun, Jean; Spatz, Alan.

In: Science Translational Medicine, Vol. 8, No. 369, 369ra177, 14.12.2016.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

van Kempen LCL, Redpath M, Elchebly M, Klein KO, Papadakis AI, Wilmott JS et al. The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene. Science Translational Medicine. 2016 Dec 14;8(369). 369ra177. https://doi.org/10.1126/scitranslmed.aai9188


BibTeX

@article{d2bc7fbae07b4524b202f741086ee033,
title = "The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene",
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.",
keywords = "Animals, Cell Cycle Proteins/genetics, Cell Line, Tumor, Chromosome Aberrations, Chromosomes, Human, X, DNA Replication, Disease Progression, Disease-Free Survival, Female, Gene Dosage, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, HEK293 Cells, Humans, Male, Melanoma/genetics, Mice, Neoplasm Metastasis, Neoplasm Transplantation, Nuclear Proteins/metabolism, Prognosis, Protein Phosphatase 2/genetics, Sex Factors, Skin Neoplasms/metabolism",
author = "{van Kempen}, {L{\'e}on C L} and Margaret Redpath and Mounib Elchebly and Klein, {Kathleen Oros} and Papadakis, {Andreas I} and Wilmott, {James S} and Scolyer, {Richard A} and Per-Henrik Edqvist and Fredrik Pont{\'e}n and Dirk Schadendorf and {van Rijk}, {Anke F} and Stefan Michiels and Anne Dumay and Anne Helbling-Leclerc and Philippe Dessen and Jasper Wouters and Marguerite Stass and Greenwood, {Celia M T} and Ghanem, {Ghanem E} and {van den Oord}, Joost and Jean Feunteun and Alan Spatz",
note = "Copyright {\circledC} 2016, American Association for the Advancement of Science.",
year = "2016",
month = "12",
day = "14",
doi = "10.1126/scitranslmed.aai9188",
language = "English",
volume = "8",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "AMER ASSOC ADVANCEMENT SCIENCE",
number = "369",

}

RIS

TY - JOUR

T1 - The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene

AU - van Kempen, Léon C L

AU - Redpath, Margaret

AU - Elchebly, Mounib

AU - Klein, Kathleen Oros

AU - Papadakis, Andreas I

AU - Wilmott, James S

AU - Scolyer, Richard A

AU - Edqvist, Per-Henrik

AU - Pontén, Fredrik

AU - Schadendorf, Dirk

AU - van Rijk, Anke F

AU - Michiels, Stefan

AU - Dumay, Anne

AU - Helbling-Leclerc, Anne

AU - Dessen, Philippe

AU - Wouters, Jasper

AU - Stass, Marguerite

AU - Greenwood, Celia M T

AU - Ghanem, Ghanem E

AU - van den Oord, Joost

AU - Feunteun, Jean

AU - Spatz, Alan

N1 - Copyright © 2016, American Association for the Advancement of Science.

PY - 2016/12/14

Y1 - 2016/12/14

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Cycle Proteins/genetics

KW - Cell Line, Tumor

KW - Chromosome Aberrations

KW - Chromosomes, Human, X

KW - DNA Replication

KW - Disease Progression

KW - Disease-Free Survival

KW - Female

KW - Gene Dosage

KW - Gene Expression Regulation, Neoplastic

KW - Genes, Tumor Suppressor

KW - HEK293 Cells

KW - Humans

KW - Male

KW - Melanoma/genetics

KW - Mice

KW - Neoplasm Metastasis

KW - Neoplasm Transplantation

KW - Nuclear Proteins/metabolism

KW - Prognosis

KW - Protein Phosphatase 2/genetics

KW - Sex Factors

KW - Skin Neoplasms/metabolism

U2 - 10.1126/scitranslmed.aai9188

DO - 10.1126/scitranslmed.aai9188

M3 - Article

VL - 8

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 369

M1 - 369ra177

ER -

ID: 76698522