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Astrocyte-specific expression of CDK4 is not sufficient for tumor formation, but cooperates with p53 heterozygosity to provide a growth advantage for astrocytes in vivo

Oncogene volume 21, pages 1325–1334 (2002)Cite this article

Abstract

The development of malignant gliomas (astrocytomas) involves the accumulation of multiple genetic changes, including mutations in the p53 and retinoblastoma (Rb) cell cycle regulatory pathways. One Rb pathway alteration seen in high-grade astrocytomas is amplification of cyclin dependent kinase-4 (CDK4). To define the function of CDK4 amplification/overexpression in astrocytoma pathogenesis, we generated three transgenic mouse lines that overexpress human CDK4 (hCDK4) in astrocytes using the human glial fibrillary acidic protein (GFAP) promoter. GFAP-hCDK4 mice do not develop brain tumors, but exhibit a small increase in astrocyte number. Cultured astrocytes from these mice do not demonstrate a cell-autonomous growth advantage in vitro and lack properties of transformed cells. To determine whether cdk4 overexpression provides a cooperative growth advantage in vitro, CDK4-overexpressing C6 glioma cell lines were generated and found to exhibit increased cell growth. In addition, GFAP-hCDK4; p53+/− as well as p53+/−; Rb+/− mice exhibited increased numbers of astrocytes compared to GFAP-hCDK4, p53+/−, or Rb+/− mice in vivo. No cooperative effect was observed with GFAP-hCDK4; Rb+/− mice. These results support the hypothesis that cdk4 overexpression alone is not sufficient for astrocytoma formation, but can provide a cooperative growth advantage in concert with genetic alterations in the p53 pathway.

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Acknowledgements

We gratefully appreciate the advice of Dr M Livia Bajenaru and the technical assistance of Ms Wen Li in our laboratory as well as Mia Nichols in The Washington University Neuroscience Transgenic Core. This work was supported by funding from The National Institutes of Health (NS41097 to DH Gutmann) and The American Cancer Society (RPG-00-231-01-CNE to DH Gutmann).

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  1. Department of Neurology, Washington University School of Medicine, St Louis, 63110, Missouri, MO, USA

    Zhi-yong Huang, Rebecca L Baldwin, Nicolé M Hedrick & David H Gutmann

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  1. Zhi-yong Huang
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  2. Rebecca L Baldwin
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Correspondence to David H Gutmann.

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Huang, Zy., Baldwin, R., Hedrick, N. et al. Astrocyte-specific expression of CDK4 is not sufficient for tumor formation, but cooperates with p53 heterozygosity to provide a growth advantage for astrocytes in vivo. Oncogene 21, 1325–1334 (2002). https://doi.org/10.1038/sj.onc.1205206

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