Cooperative p16 and p21 action protects female astrocytes from transformation
Abstract Mechanisms underlying sex differences in cancer incidence are not defined but likely involve dimorphism (s) in tumor suppressor function at the cellular and organismal levels. As an example, sexual dimorphism in retinoblastoma protein (Rb) activity was shown to block transformation of femal...
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doaj-be8f708cece04a41bfd595a9a82149a82020-11-24T21:33:24ZengBMCActa Neuropathologica Communications2051-59602018-02-016111310.1186/s40478-018-0513-5Cooperative p16 and p21 action protects female astrocytes from transformationNajla Kfoury0Tao Sun1Kwanha Yu2Nathan Rockwell3Kelsey L. Tinkum4Zongtai Qi5Nicole M. Warrington6Peter McDonald7Anuradha Roy8Scott J. Weir9Carrie A. Mohila10Benjamin Deneen11Joshua B. Rubin12Department of Pediatrics, Washington University School of MedicineDepartment of Pediatrics, Washington University School of MedicineCenter for Cell and Gene Therapy, Baylor College of MedicineDepartment of Pediatrics, Washington University School of MedicineDepartment of Pediatrics, Washington University School of MedicineDepartment of Genetics, Washington University School of MedicineDepartment of Pediatrics, Washington University School of MedicineHigh Throughput Screening Laboratory, University of KansasHigh Throughput Screening Laboratory, University of KansasUniversity of Kansas Cancer Center, University of Kansas Medical CenterDepartment of Pathology, Texas Children’s HospitalCenter for Cell and Gene Therapy, Baylor College of MedicineDepartment of Pediatrics, Washington University School of MedicineAbstract Mechanisms underlying sex differences in cancer incidence are not defined but likely involve dimorphism (s) in tumor suppressor function at the cellular and organismal levels. As an example, sexual dimorphism in retinoblastoma protein (Rb) activity was shown to block transformation of female, but not male, murine astrocytes in which neurofibromin and p53 function was abrogated (GBM astrocytes). Correlated sex differences in gene expression in the murine GBM astrocytes were found to be highly concordant with sex differences in gene expression in male and female GBM patients, including in the expression of components of the Rb and p53 pathways. To define the basis of this phenomenon, we examined the functions of the cyclin dependent kinase (CDK) inhibitors, p16, p21 and p27 in murine GBM astrocytes under conditions that promote Rb-dependent growth arrest. We found that upon serum deprivation or etoposide-induced DNA damage, female, but not male GBM astrocytes, respond with increased p16 and p21 activity, and cell cycle arrest. In contrast, male GBM astrocytes continue to proliferate, accumulate chromosomal aberrations, exhibit enhanced clonogenic cell activity and in vivo tumorigenesis; all manifestations of broad sex differences in cell cycle regulation and DNA repair. Differences in tumorigenesis disappeared when female GBM astrocytes are also rendered null for p16 and p21. These data elucidate mechanisms underlying sex differences in cancer incidence and demonstrate sex-specific effects of cytotoxic and targeted therapeutics. This has critical implications for lab and clinical research.http://link.springer.com/article/10.1186/s40478-018-0513-5Sex differencesGlioblastomaGliomaRbp16p21 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Najla Kfoury Tao Sun Kwanha Yu Nathan Rockwell Kelsey L. Tinkum Zongtai Qi Nicole M. Warrington Peter McDonald Anuradha Roy Scott J. Weir Carrie A. Mohila Benjamin Deneen Joshua B. Rubin |
spellingShingle |
Najla Kfoury Tao Sun Kwanha Yu Nathan Rockwell Kelsey L. Tinkum Zongtai Qi Nicole M. Warrington Peter McDonald Anuradha Roy Scott J. Weir Carrie A. Mohila Benjamin Deneen Joshua B. Rubin Cooperative p16 and p21 action protects female astrocytes from transformation Acta Neuropathologica Communications Sex differences Glioblastoma Glioma Rb p16 p21 |
author_facet |
Najla Kfoury Tao Sun Kwanha Yu Nathan Rockwell Kelsey L. Tinkum Zongtai Qi Nicole M. Warrington Peter McDonald Anuradha Roy Scott J. Weir Carrie A. Mohila Benjamin Deneen Joshua B. Rubin |
author_sort |
Najla Kfoury |
title |
Cooperative p16 and p21 action protects female astrocytes from transformation |
title_short |
Cooperative p16 and p21 action protects female astrocytes from transformation |
title_full |
Cooperative p16 and p21 action protects female astrocytes from transformation |
title_fullStr |
Cooperative p16 and p21 action protects female astrocytes from transformation |
title_full_unstemmed |
Cooperative p16 and p21 action protects female astrocytes from transformation |
title_sort |
cooperative p16 and p21 action protects female astrocytes from transformation |
publisher |
BMC |
series |
Acta Neuropathologica Communications |
issn |
2051-5960 |
publishDate |
2018-02-01 |
description |
Abstract Mechanisms underlying sex differences in cancer incidence are not defined but likely involve dimorphism (s) in tumor suppressor function at the cellular and organismal levels. As an example, sexual dimorphism in retinoblastoma protein (Rb) activity was shown to block transformation of female, but not male, murine astrocytes in which neurofibromin and p53 function was abrogated (GBM astrocytes). Correlated sex differences in gene expression in the murine GBM astrocytes were found to be highly concordant with sex differences in gene expression in male and female GBM patients, including in the expression of components of the Rb and p53 pathways. To define the basis of this phenomenon, we examined the functions of the cyclin dependent kinase (CDK) inhibitors, p16, p21 and p27 in murine GBM astrocytes under conditions that promote Rb-dependent growth arrest. We found that upon serum deprivation or etoposide-induced DNA damage, female, but not male GBM astrocytes, respond with increased p16 and p21 activity, and cell cycle arrest. In contrast, male GBM astrocytes continue to proliferate, accumulate chromosomal aberrations, exhibit enhanced clonogenic cell activity and in vivo tumorigenesis; all manifestations of broad sex differences in cell cycle regulation and DNA repair. Differences in tumorigenesis disappeared when female GBM astrocytes are also rendered null for p16 and p21. These data elucidate mechanisms underlying sex differences in cancer incidence and demonstrate sex-specific effects of cytotoxic and targeted therapeutics. This has critical implications for lab and clinical research. |
topic |
Sex differences Glioblastoma Glioma Rb p16 p21 |
url |
http://link.springer.com/article/10.1186/s40478-018-0513-5 |
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