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Acta Neuropathol Commun. 2018 Feb 20;6(1):12. doi: 10.1186/s40478-018-0513-5.

Cooperative p16 and p21 action protects female astrocytes from transformation.

Author information

1
Department of Pediatrics, Washington University School of Medicine, Campus Box 8208, 660 South Euclid Ave, St Louis, MO, 63110, USA.
2
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.
3
Department of Genetics, Washington University School of Medicine, St Louis, MO, USA.
4
High Throughput Screening Laboratory, University of Kansas, Lawrence, Kansas, USA.
5
University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, Kansas, USA.
6
Institute for Advancing Medical Innovation, University of Kansas Medical Center, Kansas City, Kansas, USA.
7
Department of Pathology, Texas Children's Hospital, Houston, TX, USA.
8
Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.
9
Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
10
Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA.
11
Department of Pediatrics, Washington University School of Medicine, Campus Box 8208, 660 South Euclid Ave, St Louis, MO, 63110, USA. rubin_j@wustl.edu.
12
Department of Neuroscience, Washington University School of Medicine, St Louis, USA. rubin_j@wustl.edu.

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.

KEYWORDS:

Cyclin dependent kinase inhibitors; DNA damage response; Glioblastoma; Glioma; Rb; Sex differences; p16; p21

PMID:
29458417
PMCID:
PMC5819173
DOI:
10.1186/s40478-018-0513-5
[Indexed for MEDLINE]
Free PMC Article

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