Cooperative p16 and p21 action protects female astrocytes from transformation
dc.contributor.author | Kfoury, Najla | |
dc.contributor.author | Sun, Tao | |
dc.contributor.author | Yu, Kwanha | |
dc.contributor.author | Rockwell, Nathan | |
dc.contributor.author | Tinkum, Kelsey L. | |
dc.contributor.author | Qi, Zongtai | |
dc.contributor.author | Warrington, Nicole M. | |
dc.contributor.author | McDonald, Peter R. | |
dc.contributor.author | Roy, Anuradha | |
dc.contributor.author | Weir, Scott J. | |
dc.contributor.author | Mohila, Carrie A. | |
dc.contributor.author | Deneen, Benjamin | |
dc.contributor.author | Rubin, Joshua B. | |
dc.date.accessioned | 2018-06-14T18:15:52Z | |
dc.date.available | 2018-06-14T18:15:52Z | |
dc.date.issued | 2018-02-20 | |
dc.identifier.citation | Kfoury, N., Sun, T., Yu, K., Rockwell, N., Tinkum, K. L., Qi, Z., … Rubin, J. B. (2018). Cooperative p16 and p21 action protects female astrocytes from transformation. Acta Neuropathologica Communications, 6, 12. http://doi.org/10.1186/s40478-018-0513-5 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/26519 | |
dc.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. | en_US |
dc.publisher | BioMed Central | en_US |
dc.rights | © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | Sex differences | en_US |
dc.subject | Glioblastoma | en_US |
dc.subject | Glioma | en_US |
dc.subject | Rb | en_US |
dc.subject | p16 | en_US |
dc.subject | p21 | en_US |
dc.subject | Cyclin dependent kinase inhibitors | en_US |
dc.subject | DNA damage response | en_US |
dc.title | Cooperative p16 and p21 action protects female astrocytes from transformation | en_US |
dc.type | Article | en_US |
kusw.kuauthor | McDonald, Peter R. | |
kusw.kuauthor | Roy, Anuradha | |
kusw.kudepartment | High Throughput Screening Laboratory | en_US |
dc.identifier.doi | 10.1186/s40478-018-0513-5 | en_US |
kusw.oaversion | Scholarly/refereed, publisher version | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.rights.accessrights | openAccess | en_US |
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Except where otherwise noted, this item's license is described as: © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.